Compounds useful for the treatment of diseases

ABSTRACT

The invention relates to compounds of formula (1) 
                         
and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

This invention relates to β2 agonists of general formula:

in which n and Q¹ have the meanings indicated below,and to processes for the preparation of, intermediates used in thepreparation of, compositions containing and the uses of, suchderivatives.

Adrenoceptors are members of the large G-protein coupled receptorsuper-family. The adrenoceptor subfamily is itself divided into the αand β subfamilies with the β sub-family being composed of at least 3receptor sub-types: β1, β2 and β3. These receptors exhibit differentialexpression patterns in tissues of various systems and organs of mammals.β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells(e.g. vascular, bronchial, uterine or intestinal smooth muscles),whereas β3 adrenergic receptors are mainly expressed in fat tissues(therefore β3 agonists could potentially be useful in the treatment ofobesity and diabetes) and β1 adrenergic receptors are mainly expressedin cardiac tissues (therefore β1 agonists are mainly used as cardiacstimulants).

The pathophysiology and treatments of airway diseases have beenextensively reviewed in the literature (for reference see Barnes, P. J.Chest, 1997, 111:2, pp 17S-26S and Bryan, S. A. et al, Expert Opinion oninvestigational drugs, 2000, 9:1, pp 25-42) and therefore only a briefsummary will be included here to provide some background information.

Glucocorticosteroids, anti-leukotrienes, theophylline, cromones,anti-cholinergics and β2 agonists constitute drug classes that arecurrently used to treat allergic and non-allergic airways diseases suchas asthma and chronic obstructive airways disease (COPD). Treatmentguidelines for these diseases include both short and long acting inhaledβ2 agonists. Short acting, rapid onset β2 agonists are used for “rescue”bronchodilation, whereas, long-acting forms provide sustained relief andare used as maintenance therapy.

Bronchodilation is mediated via agonism of the β2 adrenoceptor expressedon airway smooth muscle cells, which results in relaxation and hencebronchodilation. Thus, as functional antagonists, β2 agonists canprevent and reverse the effects of all bronchoconstrictor substances,including leukotriene D4 (LTD4), acetylcholine, bradykinin,prostaglandins, histamine and endothelins. Because β2 receptors are sowidely distributed in the airway, β2 agonists may also affect othertypes of cells that play a role in asthma. For example, it has beenreported that β2 agonists may stabilize mast cells. The inhibition ofthe release of bronchoconstrictor substances may be how β2 agonistsblock the bronchoconstriction induced by allergens, exercise and coldair. Furthermore, β2 agonists inhibit cholinergic neurotransmission inthe human airway, which can result in reduced cholinergic-reflexbronchoconstriction.

In addition to the airways, it has also been established that β2adrenoceptors are also expressed in other organs and tissues and thus β2agonists, such as those described in the present invention, may haveapplication in the treatment of other diseases such as, but not limitedto those of the nervous system, premature labor, congestive heartfailure, depression, inflammatory and allergic skin diseases, psoriasis,proliferative skin diseases, glaucoma and in conditions where there isan advantage in lowering gastric acidity, particularly in gastric andpeptic ulceration.

However, numerous β2 agonists are limited in their use due to their lowselectivity or adverse side-effects driven by high systemic exposure andmainly mediated through action at β2 adrenoreceptors expressed outsidethe airways (muscle tremor, tachycardia, palpitations, restlessness).Therefore there is a need for improved agents in this class.

Accordingly, there is still a need for novel β2 agonists that would havean appropriate pharmacological profile, for example in terms of potency,selectivity, duration of action and/or pharmacodynamic properties. Inthis context, the present invention relates to novel β2 agonists.

EP 0654534 B1 and EP0939134 B1 disclose a process for the preparation ofcompounds of formula (XI):

These compounds are disclosed as anti-obesity and anti-diabetic agentshaving specific β3 activity.

U.S. Pat. No. 5,561,142 discloses selective β3 agonists of formula

EP0236624 discloses compounds of formula

having anti-obesity and/or anti-hyperglycaemic activity coupled withgood selectivity from cardiac side-effects.

The invention relates to compounds of general formula (1):

wherein the (CH₂)_(n)—C(═O)Q¹ group is in position meta or para, n is 1or 2 and Q¹ is a group selected from:

and a group *—N(R⁸)-Q²-A, wherein Q² is a single bond or a C₁-C₄alkylene, R⁸ is H or C₁-C₄ alkyl, p is 1 or 2, and A is pyridyl, or agroup of formula

-   wherein R¹, R², R³, R⁴ and R⁵ are the same or different and are    selected from H, C₁-C₄ alkyl, OR⁶, SR⁶, halo, CF₃, OCF₃, COOR⁶,    SO₂NR⁶R⁷, CONR⁶R⁷, NR⁶R⁷, NHCOR⁶, wherein at least 2 of R¹ to R⁵ are    equal to H;-   wherein R⁶ and R⁷ are the same or different and are selected from H    or C₁-C₄ alkyl and the * represent the attachment point to the    carbonyl group;-   or, if appropriate, their pharmaceutically acceptable salts and/or    isomers, tautomers, solvates or isotopic variations thereof.

It has now been found that the compounds of formula (1) are agonists ofthe β2 receptors, that are particularly useful for the treatment ofβ2-mediated diseases and/or conditions, and show good potency, inparticular when administered via the inhalation route.

In the present invention, the term “potent” means that the compounds offormula (1) show an agonist potency for the β2 receptor, which is lessthan 10 nM as measured by the cell-based assay described herein.

Preferably, the compounds of the invention are selective agonists of theβ2 receptor receptors. Preferably, the compounds of the invention showan agonist potency for the β2 receptor, which is at least about 100-foldhigher as for the β3 receptor and at least about 500-fold higher as forthe β1 receptor.

In the here above general formula (1), C₁-C₄ alkyl and C₁-C₄ alkylenedenote a straight-chain or branched group containing 1, 2, 3 or 4 carbonatoms. This also applies if they carry substituents or occur assubstituents of other radicals, for example in O—(C₁-C₄)alkyl radicals,S—(C₁-C₄)alkyl radicals etc. . . . Examples of suitable (C₁-C₄)alkylradicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl. . . . Examples of suitable O—(C₁-C₄)alkylradicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy,iso-butyloxy, sec-butyloxy and tert-butyloxy. . . .

Finally, halo denotes a halogen atom selected from the group consistingof fluoro, chloro, bromo and iodo in particular fluoro or chloro.

In the following, the free bond on the phenyl group such as in thestructure below,

means that the phenyl can be substituted in the meta or para position.

The compounds of the formula (1)

can be prepared using conventional procedures such as by the followingillustrative methods in which Q¹, Q², A and n are as previously definedfor the compounds of the formula (1) unless otherwise stated.

The amide derivatives of the formula (1) may be prepared by coupling anacid of formula (2):

with an amine of formula N(R⁸)-Q²-A (3),

wherein R⁸, Q², A, p and R¹ to R⁵ are as previously defined forcompounds of formula (1)

The coupling is generally carried out in an excess of said amine as anacid receptor, with a conventional coupling agent (e.g.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride orN,N′-dicyclohexylcarbodiimide), optionally in the presence of a catalyst(e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole),and optionally in the presence of a tertiary amine base (e.g.N-methylmorpholine, triethylamine or diisopropylethylamine). Thereaction may be undertaken in a suitable solvent such as pyridine,dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethaneor ethyl acetate, and at temperature comprised between 10° C. and 40° C.(room temperature) for a period of 1-24 hours.

Said amine (3), (3′) or (3″) is either commercially available or may beprepared by conventional methods well known to the one skilled in theart (e.g. reduction, oxidation, alkylation, protection, deprotectionetc. . . ) from commercially available material.

The acid of formula (2) may be prepared from the corresponding ester offormula (4):

wherein Ra is a suitable acid protecting group, preferably a(C₁-C₄)alkyl group, which includes, but is not limited to, methyl andethyl, according to any method well-known to the one skilled in the artto prepare an acid from an ester, without modifying the rest of themolecule. For example, the ester may be hydrolysed by treatment withaqueous acid or base (e.g. hydrogen chloride, potassium hydroxide,sodium hydroxide or lithium hydroxide), optionally in the presence of asolvent or mixture of solvents (e.g. water, 1,4-dioxan,tetrahydrofuran/water), at a temperature comprised between 20° C. and100° C., for a period of 1 to 40 hours.

The ester of formula (4) may be prepared by reaction of an amine offormula (5):

wherein Ra and n are as previously defined, with a bromide of formula(6):

In a typical procedure, the amine of formula (5) is reacted with abromide of formula (6) optionally in the presence of a solvent ormixture of solvents (e.g. dimethyl sulphoxide, toluene,N,N-dimethylformamide, acetonitrile), optionally in the presence of asuitable base (e.g. triethylamine, diisopropylethylamine, potassiumcarbonate) at a temperature comprised between 80° C. and 120° C., for 12to 48 hours.

The bromide of formula (6) may be prepared from the ester of formula(7):

according to any method well-known to the one skilled in the art toprepare an alcohol from an ester, without modifying the rest of themolecule.

In a typical procedure, the ester of formula (7) is reduced with boranedimethylsulfide complex in tetrahydrofuran at a reflux for a period of 2hours.

The alcohol of formula (7) may be prepared as either the (R) or (S)enantiomer according to methods well described in the literature(Tetrahedron Letters 1994, 35(50), 9375).

The amine of formula (5) may be prepared as either the (R) or (S)enantiomer from the corresponding protected amine of formula (8):

wherein Ra and n are as previously defined and Rb and Rc represent anysuitable substituents so that HNRbRc is a chiral amine (for example, Rbmay be hydrogen and Rc may be α-methylbenzyl), provided that the bondsbetween N and Rb and N and Rc can be easily cleaved to give the freeamine of formula (5) using standard methodology for cleaving nitrogenprotecting groups, such as those found in the text book T. W. GREENE,Protective Groups in Organic Synthesis, A. Wiley-IntersciencePublication, 1981.

The amine of formula (8) may be prepared as a single diastereomer byreaction of an amine of formula HNRbRc with a ketone of formula (9):

wherein Ra, Rb, Rc and n are as previously defined.

In a typical procedure, the reaction of the ketone of formula (9) withthe amine of formula HNRbRc leads to a chiral intermediate which is inturn reduced by a suitable reducing agent (e.g. sodium cyanoborohydrideof formula NaCNBH₃ or sodium triacetoxyborohydride of formulaNa(OAc)₃BH) optionally in the presence of a drying agent (e.g. molecularsieves, magnesium sulfate) and optionally in the presence of an acidcatalyst (e.g. acetic acid) to give the amine of formula (8) as amixture of diastereomers. The reaction is generally done in a solventsuch as tetrahydrofuran or dichloromethane at a temperature comprisedbetween 20° C. and 80° C. for 3 to 72 hours. The resulting product isthen converted to the hydrochloride salt and selectively crystallisedfrom a suitable solvent or mixture of solvents (e.g. isopropanol,ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) togive (8) as a single diastereomer.

The ketone of formula (9) where n=1 may be prepared by palladiummediated coupling of an aryl halide of formula (10):

wherein Ra is as previously defined and Hal represents an halogen atom,which includes, but is not limited to bromo and iodo, with an enolate orenolate equivalent.

In a typical procedure, the aryl halide of formula (10) is reacted witha tin enolate generated in-situ by treatment of isoprenyl acetate withtri-n-butyltin methoxide of formula Bu₃SnOMe in the presence of asuitable palladium catalyst (palladium acetate/tri-ortho-tolylphosphineof formula Pd(OAc)₂/P(o-Tol)₃) in a non-polar solvent (e.g. toluene,benzene, hexane). Preferably, the reaction is carried out at atemperature comprised between 80° C. and 110° C. for 6 to 16 hours.

The aryl halide of formula (10) may be obtained by esterification of thecorresponding acid of formula (11):

wherein Hal is as previously defined,

-   according to any method well-known to the one skilled in the art to    prepare an ester from an acid, without modifying the rest of the    molecule.

In a typical procedure, the acid of formula (11) is reacted with analcoholic solvent of formula RaOH, wherein Ra is as previously defined,in the presence of an acid such as hydrogen chloride at a temperaturebetween 10° C. and 40° C. (room temperature) for 8 to 16 hours.

The acid of formula (11) is a commercial product.

The ketone of formula (9) where n=2 may be prepared by reduction of analkene of formula (12):

In a typical procedure, a solution of the olefin of formula (12) in asuitable solvent (e.g. methanol, ethanol, ethyl acetate) is treated witha palladium catalyst (e.g. 10% palladium on charcoal) and stirred underan atmosphere of hydrogen, optionally at elevated pressure (e.g. 60psi), at temperature between room temperature and 60° C. for 8-24 hours.

The alkene of formula (12) may be prepared by a palladium mediatedcoupling of an activated olefin with an aryl halide of formula (13):

In a typical procedure, the aryl halide (13) is coupled with a vinylester (e.g. methyl acrylate) in the presence of a suitable palladiumcatalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formulaPd(PPh₃)₄, palladium acetate/tri-ortho-tolylphosphine of formulaPd(OAc)₂/P(o-tol)₃ or (diphenylphosphino)ferrocenyl palladium chlorideof formula dppfPdCl₂) in a sutiable solvent (e.g. acetonitrile,N,N-dimethylformamide, toluene), optionally in the presence of a basesuch as triethylamine at a temperature between 40° C. and 110° C. for 8to 24 hours.

The ketone of formula (13) is a commercial product.

For some of the steps of the here above described process of preparationof the compounds of formula (1), it may be necessary to protectpotential reactive functions that are not wished to react, and to cleavesaid protecting groups in consequence. In such a case, any compatibleprotecting radical can be used. In particular methods of protection anddeprotection such as those described by T. W. GREENE (Protective Groupsin Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P.J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can beused.

All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well-knownto those skilled in the art with reference to literature precedents andthe examples and preparations hereto.

Also, the compounds of formula (1) as well as intermediate for thepreparation thereof can be purified according to various well-knownmethods, such as for example crystallization or chromatography.

Compounds of formula (1) wherein n is 1 or 2, Q¹ is a group *—NH-Q²-A,wherein Q² is C₁-C₄ alkylene and A is group of formula

wherein R¹, R², R³, R⁴ and R⁵ are as defined above, are particularlypreferred.

Preferably n is 1.

Preferably, Q² is selected from —CH₂—, —(CH₂)₂—, —(CH₂)₃— and —CH(CH₃)—.

More preferably, Q² is —CH₂—.

Preferably, R¹, R², R³, R⁴ and R⁵ are the same or different and areselected from H, C₁-C₄ alkyl, OR⁶, Cl, F, CF₃, OCF₃, COOR⁶, SO₂NR⁶R⁷,provided at least 2 of R¹ to R⁵ are equal to H, wherein R⁶ and R⁷ arethe same or different and are selected from H or C₁-C₄ alkyl.

Preferably, R¹, R², R³, R⁴ and R⁵ are the same or different and areselected from H, CH₃, OH, OCH₃, OCH₂CH₃, Cl, F, CF₃, OCF₃, COOH, SO₂NH₂,provided at least 2 of R¹ to R⁵ are equal to H.

Preferably, R¹, R², R³, R⁴ and R⁵ are the same or different and areselected from H, CH₃, OH, OCH₃, OCH₂CH₃, Cl, F, CF₃, OCF₃, COOH, SO₂NH₂,provided at least 3 of R¹ to R⁵ are equal to H.

Preferably, R¹, R², R³, R⁴ and R⁵ are selected from Cl, provided atleast 3 of R¹ to R⁵ are equal to H.

Other preferred compounds are those wherein n is 1 or 2 and Q¹ is

-   wherein p is 1 or 2, R¹, R², R³ and R⁴ are the same or different and    are selected from H, C₁-C₄ alkyl, OR⁶, SR⁶, halo, CF₃, OCF₃, COOR⁶,    SO₂NR⁶R⁷, CONR⁶R⁷, NR⁶R⁷, NHCOR⁶, provided at least 2 of R¹ to R⁴    are equal to H;-   wherein R⁶ and R⁷ are the same or different and are selected from H    or C₁-C₄ alkyl.

Preferably, R¹, R², R³, and R⁴ are the same or different and areselected from H and OR⁶, provided at least 2 of R¹ to R⁴ are equal to H.

Other preferred compounds are those wherein n is 1 or 2 and Q¹ is

Other preferred compounds are those wherein n is 1 or 2 and Q¹ is agroup *—NH-Q²-A, wherein Q² is C₁-C₄ alkylene and A is pyridin-2-yl.

Other preferred compounds are those wherein n is 1 or 2 and Q¹ is agroup *—NH-Q²-A, wherein Q² is C₁-C₄ alkylene and A is naphthyl.

Particularly preferred are the compounds of the formula (1) as describedin the Examples section hereafter, i.e.:

-   N-(2,6-Dimethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-(2-Ethoxybenzyl    )-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-(2-Hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-indan-2-yl-acetamide;-   N-(3,4-Dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-[4-(Aminosulfonyl)benzyl]-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(pyridin-2-ylmethyl)-acetamide;-   4-{(2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetylamino)-methyl}-benzamide;-   N-(3,4-Dimethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-trifluoromethoxybenzyl)-acetamide;-   N-(2-Chloro,    6-fluorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-(3,4-Dimethylbenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-[2-Fluoro-5-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-(2,6-Dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-phenylethyl)acetamide;-   N-Benzyl-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylaqmino]-propyl}-phenyl)-acetamide;-   N-(3,5-Dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   N-(4-Chlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;-   4-{([2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoic    acid;-   2-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1R)-1-phenylethyl]acetamide;-   4-{(1R)-2-[((1R)-2-{3-[2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   4-{(1R)-2-[((1R)-2-{3-[2-(7-Ethoxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-[2-(4-Chlorophenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;-   N-[2-(4-Ethylphenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;-   N-(1,1-Dimethyl-2-phenylethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;-   N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;-   N-(3,4-Difluorobenzyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;-   4-{(1R)-2-[((1R)-2-{3-[2-(1,3-Dihydro-2H-isoindol-2-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   2-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylacetamide;-   2-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1-naphthylmethyl)acetamide;-   N-(3,4-Dichlorobenzyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;-   2-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-pyridin-2-ylethyl)acetamide;-   2-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(2R)-2-phenylpropyl]acetamide;-   N-Benzyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;-   N-[3-(4-Fluorophenyl)propyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;-   N-(2,6-Dichlorobenzyl)-3-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanamide;-   N-(2,6-Dimethoxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   N-(2-Ethoxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   N-(3,4-Dimethylbenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   N-(2,3-Dihydro-1H-inden-2-yl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   4-{(1R)-2-[((1R)-2-{3-[3-(3,4-Dihydroisoquinolin-2-(1H)-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-(2-Chloro-6-fluorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   N-(2-Chlorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   3-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(pyridin-2-ylmethyl)propanamide;-   N-(2-Chlorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   3-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(pyridin-2-ylmethyl)propanamide;-   N-Benzyl-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   3-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)propanamide;-   3-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3-phenylpropyl)propanamide;-   4-{(1R)-2-[((1R)-2-{3-[3-(1,3-Dihydro-2H-isoindol-2-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-[2-Fluoro-5-(trifluoromethyl)benzyl]-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   N-(2-Hydroxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;-   3-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylpropanamide;-   N-Benzyl-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)acetamide;-   2-(4-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)-N-(3-phenyl-propyl)acetamide;-   2-(4-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)-N-indan-2-yl-acetamide;-   1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)ethanone;-   N-(2-Hydroxybenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide;-   N-(3-Chlorobenzyl)-2-(4-{-(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide;-   N-(4-Chlorobenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide;-   2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(2-methoxybenzyl)-acetamide;-   2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)-N-(3-methoxybenzyl)acetamide;-   2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(4-methoxybenzyl)-acetamide;-   N-(2,6-Dimethoxybenzyl)-2-(4-{(2R)-2-[(2R-2-hydroxy-2-(4-hydroxy-3-hydroxy-menthylphenyl)-ethylamino]propyl}phenyl)-acetamide,-   2-(4-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethyl-amino]propyl}phenyl)-N-(pyridin-2-ylmethyl)acetamide,-   N-[2-Fluoro-5-(trifluoromethyl)benzyl]-2-{4-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide,    and,-   2-{4-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)acetamide.

According to one aspect of the present invention, the compounds offormula (1) wherein the (CH₂)_(n)—C(═O)Q¹ group is in position meta aregenerally preferred.

The compounds of formula (1) may also be optionally transformed intopharmaceutically acceptable salts. In particular, these pharmaceuticallyacceptable salts of the compounds of the formula (1) include the acidaddition and the base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate,isethionate, D- and L-lactate, malate, maleate, malonate, mesylate,methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, oxalate,palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen,saccharate, stearate, succinate, D- and L-tartrate,1-hydroxy-2-naphthoate and tosylate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Stahl and Wermuth, Handbook ofPharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH,Weinheim, Germany (2002).

Pharmaceutically acceptable salts of compounds of formula (1) may beprepared by one or more of three methods:

-   (i) by reacting the compound of formula (1) with the desired acid or    base;-   (ii) by removing an acid- or base-labile protecting group from a    suitable precursor of the compound of formula (1) or by ring-opening    a suitable cyclic precursor, for example, a lactone or lactam, using    the desired acid or base; or-   (iii) by converting one salt of the compound of formula (1) to    another by reaction with an appropriate acid or base or by means of    a suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of formula (1) includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of formula (1) ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula (1).

As indicated, so-called ‘pro-drugs’ of the compounds of formula (1) arealso within the scope of the invention. Thus certain derivatives ofcompounds of formula (1) which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into compounds of formula (1) having the desired activity, forexample, by hydrolytic cleavage. Such derivatives are referred to as‘prodrugs’. Further information on the use of prodrugs may be found in‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T.Higuchi and W. Stella) and ‘Bioreversible Carriers in Drug Design’,Pergamon Press, 1987 (ed. E. B Roche, American PharmaceuticalAssociation).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (1) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by H.Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include:

-   (i) where the compound of formula (1) contains a carboxylic acid    functionality (—COOH), an ester thereof, for example, a compound    wherein the hydrogen of the carboxylic acid functionality of the    compound of formula (1) is replaced by (C₁-C₈)alkyl;-   (ii) where the compound of formula (1) contains an alcohol    functionality (—OH), an ether thereof, for example, a compound    wherein the hydrogen of the alcohol functionality of the compound of    formula (1) is replaced by (C₁-C₆)alkanoyloxymethyl; and-   (iii) where the compound of formula (1) contains a primary or    secondary amino functionality (—NH₂ or —NHR where R≠H), an amide    thereof, for example, a compound wherein, as the case may be, one or    both hydrogens of the amino functionality of the compound of    formula (1) is/are replaced by (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of formula (1) may themselves act asprodrugs of other compounds of formula (1).

Also included within the scope of the invention are metabolites ofcompounds of formula (1), that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include

-   (i) where the compound of formula (1) contains a methyl group, an    hydroxymethyl derivative thereof (—CH₃->—CH₂OH):-   (ii) where the compound of formula (1) contains an alkoxy group, an    hydroxy derivative thereof (—OR->—OH);-   (iii) where the compound of formula (1) contains a tertiary amino    group, a secondary amino derivative thereof (—NR¹R²->—NHR¹ or    —NHR²);-   (iv) where the compound of formula (1) contains a secondary amino    group, a primary derivative thereof (—NHR¹->—NH₂);-   (v) where the compound of formula (1) contains a phenyl moiety, a    phenol derivative thereof (-Ph->-PhOH); and-   (I).(vi) where the compound of formula (1) contains an amide group,    a carboxylic acid derivative thereof (—CONH₂->COOH).

Compounds of formula (1) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (1)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where the compound contains, for example, a ketoor structural isomers are interconvertible via a low oxime group or anaromatic moiety, energy barrier, tautomeric isomerism (‘tautomerism’)can occur. This can take the form of proton tautomerism in compounds offormula (1) containing, for example, an imino, keto, or oxime group, orso-called valence tautomerism in compounds which contain an aromaticmoiety. It follows that a single compound may exhibit more than one typeof isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (1), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (1) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, “Stereochemistry ofOrganic Compounds” by E. L. Eliel (Wiley, N.Y., 1994).

According to one aspect of the present invention, the (R,R)-stereoisomerof the formula below is generally preferred:

wherein n and Q¹ are as defined above for compounds of formula (1).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (1) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula (1), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (1) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

The compounds of formula (1), their pharmaceutically acceptable saltsand/or derived forms, are valuable pharmaceutically active compounds,which are suitable for the therapy and prophylaxis of numerous disordersin which the β2 receptor is involved or in which agonism of thisreceptor may induce benefit, in particular the allergic and non-allergicairways diseases but also in the treatment of other diseases such as,but not limited to those of the nervous system, premature labor,congestive heart failure, depression, inflammatory and allergic skindiseases, psoriasis, proliferative skin diseases, glaucoma and inconditions where there is an advantage in lowering gastric acidity,particularly in gastric and peptic ulceration.

The compounds of formula (1) and their pharmaceutically acceptable saltsand derived forms as mentioned above can be administered according tothe invention to animals, preferably to mammals, and in particular tohumans, as pharmaceuticals for therapy and/or prophylaxis. They can beadministered per se, in mixtures with one another or in the form ofpharmaceutical preparations which as active constituent contain anefficacious dose of at least one compounds of formula (1), itspharmaceutically acceptable salts and/or derived forms, in addition tocustomary pharmaceutically innocuous excipients and/or additives.

The compounds of formula (1), their pharmaceutically acceptable saltsand/or derived forms may be freeze-dried, spray-dried, or evaporativelydried to provide a solid plug, powder, or film of crystalline oramorphous material. Microwave or radio frequency drying may be used forthis purpose.

The compounds of formula (1), their pharmaceutically acceptable saltsand/or derived forms may be administered alone or in combination withother drugs and will generally be administered as a formulation inassociation with one or more pharmaceutically acceptable excipients. Theterm “excipient” is used herein to describe any ingredient other thanthe compound of the invention. The choice of excipient will to a largeextent depend on the particular mode of administration.

Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films, ovules, sprays and liquidformulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 weight % to 5 weight % of the tablet, and glidants may comprise from0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight %to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound offormula (1), a film-forming polymer, a binder, a solvent, a humectant, aplasticiser, a stabiliser or emulsifier, a viscosity-modifying agent anda solvent. Some components of the formulation may perform more than onefunction.

The compound of formula (1) may be water-soluble or insoluble. Awater-soluble compound typically comprises from 1 weight % to 80 weight%, more typically from 20 weight % to 50 weight %, of the solutes. Lesssoluble compounds may comprise a greater proportion of the composition,typically up to 88 weight % of the solutes. Alternatively, the compoundof formula (1) may be in the form of multiparticulate beads.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange 0.01 to 99 weight %, more typically in the range 30 to 80 weight%.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Pharmaceutical Technology On-line,25(2), 1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (1) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents andPGLApoly(dl-lactic-coglycolic)acid (PGLA) microspheres.

Topical Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958 by Finninand Morgan (October 1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Inhaled/Intranasal Administration

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as I-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of formula (1), propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 0.001 mg to 10 mg of the compoundof formula (1). The overall daily dose will typically be in the range0.001 mg to 40 mg which may be administered in a single dose or, moreusually, as divided doses throughout the day.

The compounds of formula (1) are particularly suitable for anadministration by inhalation

Rectal/Intravaginal Administration

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Ocular/Aural Administration

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

Other Technologies

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Kit-of-Parts

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (1) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example parenteral, for administering theseparate compositions at different dosage intervals, or for titratingthe separate compositions against one another. To assist compliance, thekit typically comprises directions for administration and may beprovided with a so-called memory aid.

Dosage

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range 0.001 mg to 5000 mgdepending, of course, on the mode of administration. For example, anintravenous daily dose may only require from 0.001 mg to 40 mg. Thetotal daily dose may be administered in single or divided doses and may,at the physician's discretion, fall outside of the typical range givenherein.

These dosages are based on an average human subject having a weight ofabout 65 kg to 70 kg. The physician will readily be able to determinedoses for subjects whose weight falls outside this range, such asinfants and the elderly.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

According to another embodiment of the present invention, the compoundsof the formula (1), or pharmaceutically acceptable salts, derived formsor compositions thereof, can also be used as a combination with one ormore additional therapeutic agents to be co-administered to a patient toobtain some particularly desired therapeutic end result such as thetreatment of pathophysiologically-relevant disease processes including,but not limited to (i) bronchoconstriction, (ii) inflammation, (iii)allergy, (iv) tissue destruction, (v) signs and symptoms such asbreathlessness, cough. The second and more additional therapeutic agentsmay also be a compound of formula (1), or a pharmaceutically acceptablesalt, derived forms or compositions thereof, or one or more β2 agonistsknown in the art. More typically, the second and more therapeutic agentswill be selected from a different class of therapeutic agents.

As used herein, the terms “co-administration”, “co-administered” and “incombination with”, referring to the compounds of formula (1) and one ormore other therapeutic agents, is intended to mean, and does refer toand include the following:

-   -   simultaneous administration of such combination of compound(s)        of formula (1) and therapeutic agent(s) to a patient in need of        treatment, when such components are formulated together into a        single dosage form which releases said components at        substantially the same time to said patient,    -   substantially simultaneous administration of such combination of        compound(s) of formula (1) and therapeutic agent(s) to a patient        in need of treatment, when such components are formulated apart        from each other into separate dosage forms which are taken at        substantially the same time by said patient, whereupon said        components are released at substantially the same time to said        patient,    -   sequential administration of such combination compound(s) of        formula (1) and therapeutic agent(s) to a patient in need of        treatment, when such components are formulated apart from each        other into separate dosage forms which are taken at consecutive        times by said patient with a significant time interval between        each administration, whereupon said components are released at        substantially different times to said patient; and    -   sequential administration of such combination of compound(s) of        formula (1) and therapeutic agent(s) to a patient in need of        treatment, when such components are formulated together into a        single dosage form which releases said components in a        controlled manner whereupon they are concurrently,        consecutively, and/or overlapingly administered at the same        and/or different times by said patient,        where each part may be administered by either the same or        different route.

Suitable examples of other therapeutic agents which may be used incombination with the compound(s) of formula (1), or pharmaceuticallyacceptable salts, derived forms or compositions thereof, include, butare by no means limited to:

-   (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating    protein (FLAP) antagonists,-   (b) Leukotriene antagonists (LTRAs) including antagonists of LTB₄,    LTC₄, LTD₄, and LTE₄,-   (c) Histamine receptor antagonists including H1 and H3 antagonists,-   (d) α₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic    agents for decongestant use,-   (e) muscarinic M3 receptor antagonists or anticholinergic agents,-   (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,-   (g) Theophylline,-   (h) Sodium cromoglycate,-   (i) COX inhibitors both non-selective and selective COX-1 or COX-2    inhibitors (NSAIDs),-   (j) Oral and inhaled glucocorticosteroids,-   (k) Monoclonal antibodies active against endogenous inflammatory    entities,-   (l) Anti-tumor necrosis factor (anti-TNF-α) agents,-   (m) Adhesion molecule inhibitors including VLA-4 antagonists,-   (n) Kinin-B₁- and B₂-receptor antagonists,-   (o) Immunosuppressive agents,-   (p) Inhibitors of matrix metalloproteases (MMPs),-   (q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,-   (r) Elastase inhibitors,-   (s) Adenosine A2a receptor agonists,-   (t) Inhibitors of urokinase,-   (u) Compounds that act on dopamine receptors, e.g. D2 agonists,-   (v) Modulators of the NFκβ pathway, e.g. IKK inhibitors,-   (w) modulators of cytokine signalling pathyways such as p38 MAP    kinase or syk kinase,-   (x) Agents that can be classed as mucolytics or anti-tussive, and-   (y) Antibiotics.

According to the present invention, combination of the compounds offormula (1) with:

-   -   glucocorticosteroids, in particular inhaled glucocorticosteroids        with reduced systemic side effects, including prednisone,        prednisolone, flunisolide, triamcinolone acetonide,        beclomethasone dipropionate, budesonide, fluticasone propionate,        ciclesonide, and mometasone furoate, or    -   muscarinic M3 receptor antagonists or anticholinergic agents        including in particular ipratropium salts, namely bromide,        tiotropium salts, namely bromide, oxitropium salts, namely        bromide, perenzepine, and telenzepine,        are preferred.

It is to be appreciated that all references herein to treatment includecurative, palliative and prophylactic treatment. The description, whichfollows, concerns the therapeutic applications to which the compounds offormula (1) may be put.

The compounds of formula (1) have the ability to interact with the β2receptor and thereby have a wide range of therapeutic applications, asdescribed further below, because of the essential role which the β2receptor plays in the physiology of all mammals.

Therefore, a further aspect of the present invention relates to thecompounds of formula (1), or pharmaceutically acceptable salts, derivedforms or compositions thereof, for use in the treatment of diseases,disorders, and conditions in which the β2 receptor is involved. Morespecifically, the present invention also concerns the compounds offormula (1), or pharmaceutically acceptable salts, derived forms orcompositions thereof, for use in the treatment of diseases, disorders,and conditions selected from the group consisting of:

-   -   asthma of whatever type, etiology, or pathogenesis, in        particular asthma that is a member selected from the group        consisting of atopic asthma, non-atopic asthma, allergic asthma,        atopic bronchial IgE-mediated asthma, bronchial asthma,        essential asthma, true asthma, intrinsic asthma caused by        pathophysiologic disturbances, extrinsic asthma caused by        environmental factors, essential asthma of unknown or inapparent        cause, non-atopic asthma, bronchitic asthma, emphysematous        asthma, exercise-induced asthma, allergen induced asthma, cold        air induced asthma, occupational asthma, infective asthma caused        by bacterial, fungal, protozoal, or viral infection,        non-allergic asthma, incipient asthma, wheezy infant syndrome        and bronchiolytis,    -   chronic or acute bronchoconstriction, chronic bronchitis, small        airways obstruction, and emphysema,    -   obstructive or inflammatory airways diseases of whatever type,        etiology, or pathogenesis, in particular an obstructive or        inflammatory airways disease that is a member selected from the        group consisting of chronic eosinophilic pneumonia, chronic        obstructive pulmonary disease (COPD), COPD that includes chronic        bronchitis, pulmonary emphysema or dyspnea associated or not        associated with COPD, COPD that is characterized by        irreversible, progressive airways obstruction, adult respiratory        distress syndrome (ARDS), exacerbation of airways        hyper-reactivity consequent to other drug therapy and airways        disease that is associated with pulmonary hypertension,    -   bronchitis of whatever type, etiology, or pathogenesis, in        particular bronchitis that is a member selected from the group        consisting of acute bronchitis, acute laryngotracheal        bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus        bronchitis, dry bronchitis, infectious asthmatic bronchitis,        productive bronchitis, staphylococcus or streptococcal        bronchitis and vesicular bronchitis,    -   acute lung injury,    -   bronchiectasis of whatever type, etiology, or pathogenesis, in        particular bronchiectasis that is a member selected from the        group consisting of cylindric bronchiectasis, sacculated        bronchiectasis, fusiform bronchiectasis, capillary        bronchiectasis, cystic bronchiectasis, dry bronchiectasis and        follicular bronchiectasis.

A still further aspect of the present invention also relates to the useof the compounds of formula (1), or pharmaceutically acceptable salts,derived forms or compositions thereof, for the manufacture of a drughaving a β2 agonist activity. In particular, the present inventionsconcerns the use of the compounds of formula (1), or pharmaceuticallyacceptable salts, derived forms or compositions thereof, for themanufacture of a drug for the treatment of β2-mediated diseases and/orconditions, in particular the diseases and/or conditions listed above.

As a consequence, the present invention provides a particularlyinteresting method of treatment of a mammal, including a human being,including treating said mammal with an effective amount of a compound offormula (1), or a pharmaceutically acceptable salt, derived form orcomposition thereof. More precisely, the present invention provides aparticularly interesting method of treatment of a mammal, including ahuman being, to treat a β2-mediated diseases and/or conditions, inparticular the diseases and/or conditions listed above, includingtreating said mammal with an effective amount of a compound of formula(1), its pharmaceutically acceptable salts and/or derived forms.

The following examples illustrate the preparation of the compounds ofthe formula (1):

EXAMPLE 1N-(2,6-Dimethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

A solution of2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2,6-dimethoxybenzyl)-acetamide(Preparation 1) (125 mg, 0.20 mmol) in methanol (6 ml) was treated withacetic acid (6 ml) and ammonium fluoride (74 mg, 2.0 mmol) and thereaction heated to 40° C. for 16 hours. The solvent was removed in vacuoand the residue purified by flash column chromatography on silica geleluting with dichloromethane:methanol:880 ammonia (95:5:0.5 changing to93:7:0.7, by volume) to give the title compound as a white solid aftertrituration with diethyl ether (59 mg).

¹H NMR (400 MHz, CD₃OD): δ=7.24-7.15 (3H, m), 7.09-7.07 (1H, m),7.02-6.97 (3H, m), 6.70-6.68 (1H, d), 6.61-6.59 (2H, d), 4.61 (2H, s),4.61-4.58 (1H, m), 4.41 (2H, s), 3.75 (6H, s), 3.43 (2H, s), 2.92-2.84(2H, m), 2.71-2.67 (2H, m), 2.57-2.52 (1H, dd), 1.05-1.03 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 509, [M−H]⁻ 507.

CHN analysis: Found: C, 67.00%; H, 7.48%; N, 5.11%.C₂₉H₃₆N₂O₆+0.2Et₂O+0.6H₂O requires C, 67.00%; H, 7.40%; N, 5.24%.

EXAMPLE 2N-(2-Ethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-ethoxybenzyl)-acetamide (Preparation 2) according to the method for example 1to give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.22-7.18 (3H, m), 7.13-7.11 (2H, d), 7.07(1H, s), 7.03-7.01 (2H, d), 6.90-6.88 (1H, d), 6.85-6.81 (1H, t),6.71-6.69 (1H, d), 4.65-4.59 (1H, m), 4.62 (2H, s), 4.35 (2H, s),4.03-3.98 (2H, q), 3.50 (2H, s), 2.99-2.85 (2H, m), 2.77-2.70 (2H, m),2.59-2.54 (1H, dd), 1.34-1.31 (3H, t), 1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 493, [M−H]⁻ 491.

CHN analysis: Found: C, 69.25%; H, 7.59%; N, 5.31%.C₂₉H₃₆N₂O₅+0.15Et₂O+0.55H₂O requires C, 69.22%; H, 7.57%; N, 5.45%.

EXAMPLE 3N-(2-Hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-hydroxybenzyl)-acetamide (Preparation 3) according to the method for example 1,using water instead of acetic acid as the co-solvent, to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.23 (1H, S), 7.19-7.17 (1H, d), 7.12-7.00(6H, m), 6.77-6.73 (2H, t), 6.71-6.69 (1H, d), 4.65-4.60 (1H, m), 4.62(2H, s), 4.32 (2H, s), 3.50 (2H, s), 3.00-2.86 (2H, m), 2.75-2.70 (2H,m), 2.60-2.55 (1H, m), 1.07-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 465, [M+Na]⁺ 487, [M−H]⁻ 463.

CHN analysis: Found: C, 67.46%; H, 7.03%; N, 5.66%. C₂₇H₃₂N₂O₅+0.9H₂Orequires C, 67.45%; H, 7.09%; N, 5.83%.

EXAMPLE 42-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-indan-2-yl-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-indan-2-yl-acetamide(Preparation 4) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.22-7.16 (4H, m), 7.14-7.09 (3H, m), 7.05(1H, S), 7.03-6.99 (2H, t), 6.70-6.68 (1H, d), 4.63-4.60 (1H, t), 4.61(2H, s), 4.57-4.53 (1H, m), 3.43 (2H, s), 3.25-3.20 (2H, dd), 2.98-2.93(1H, q), 2.90-2.85 (1H, dd), 2.84-2.79 (2H, dd), 2.74-2.69 (2H, m),2.60-2.55 (1H, dd), 1.08-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 475, [M−H]³¹ 473.

CHN analysis: Found: C, 72.29%; H, 7.28%; N, 5.79%. C₂₉H₃₄N₂O₄+0.4H₂Orequires C, 72.29%; H, 7.28%; N, 5.81%.

EXAMPLE 5N-(3,4-Dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,4-dichlorobenzyl)-acetamide (Preparation 5) according to the method for example 3to give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.41-7.38 (1H, d), 7.33 (1H, d), 7.21-7.17(2H, m), 7.13-7.11 (2H, d), 7.06 (1H, s), 7.01-6.99 (2H, m), 6.69-6.67(1H, d), 4.60 (2H, s), 4.60-4.57 (1H, m), 4.30 (2H, s), 3.50 (2H, s),2.96-2.91 (1H, m), 2.88-2.83 (1H, dd), 2.73-2.68 (2H, m), 2.60-2.57 (1H,dd), 1.06-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 517/519, [M−H]⁻ 515/517.

CHN analysis: Found: C, 61.95%; H, 5.93%; N, 5.37%.C₂₇H₃₀Cl₂N₂O₄+0.35H₂O requires C, 61.92%; H, 5.91%; N, 5.35%.

EXAMPLE 6N-[4-(Aminosulfonyl)benzyl]-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-[4-(aminosulfonyl)benzyl]-acetamide(Preparation 6) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.82-7.79 (2H, d), 7.38-7.36 (2H, d),7.25-7.13 (3H, m), 7.09 (1H, s), 7.05-7.03 (2H, d), 6.72-6.70 (1H, d),4.65-4.62 (1H, m), 4.62 (2H, s), 4.42 (2H, s), 3.53 (2H, s), 3.04-2.98(1H, m), 2.93-2.86 (1H, m), 2.80-2.75 (2H, m), 2.63-2.57 (1H, m),1.09-1.08 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 528, [M+Na]⁺ 550, [M−H]⁻ 526.

CHN analysis: Found: C, 59.44%; H, 6.44%; N, 7.65%. C₂₇H₃₃N₃O₆S+1.0H₂Orequires C, 59.43%; H, 6.47%; N, 7.70%.

EXAMPLE 72-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(pyridin-2-ylmethyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(pyridin-2-ylmethyl)-acetamide(Preparation 7) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=8.44-8.42 (1H, d), 7.75-7.71 (1H, t),7.28-7.14 (5H, m), 7.11 (1H, s), 7.04-7.01 (2H, t), 6.70-6.68 (1H, d),4.63-4.60 (1H, m), 4.62 (2H, s), 4.47 (2H, s), 3.57 (2H, s), 3.03-2.95(1H, m), 2.91-2.86 (1H, dd), 2.77-2.72 (2H, m), 2.64-2.59 (1H, dd),1.11-1.09 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 450, [M+Na]⁺ 472, [M−H]⁻ 448.

CHN analysis: Found: C, 67.06%; H, 6.94%; N, 8.96%. C₂₆H₃₁N₃O₄+0.9H₂Orequires C, 67.05%; H, 7.10%; N, 9.02%.

EXAMPLE 84-{(2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetylamino)-methyl}-benzamide

Prepared from4-{(2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetylamino)-methyl}-benzamide(Preparation 8) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.80-7.78 (2H, d), 7.31-7.29 (2H, d),7.21-7.12 (3H, m), 7.09 (1H, s), 7.03-7.01 (2H, d), 6.70-6.68 (1H, d),4.61-4.59 (1H, m), 4.61 (2H, s), 4.40 (2H, s), 3.52 (2H, s), 2.98-2.94(1H, m), 2.90-2.85 (1H, m), 2.74-2.70 (2H, m), 2.61-2.56 (1H, dd),1.08-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 492, [M+Na]⁺ 514, [M−H]⁻ 490.

CHN analysis: Found: C, 65.27%; H, 6.73%; N, 8.20%. C₂₈H₃₃N₃O₅+1.3H₂Orequires C, 65.30%; H, 6.97%; N, 8.16%.

EXAMPLE 9N-(3,4-Dimethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,4-dimethoxybenzyl)-acetamide (Preparation 9) according to the method for example 3to give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.13 (3H, m), 7.08 (1H, s), 7.02-7.00(2H, d), 6.86-6.77 (3H, m), 6.70-6.68 (1H, d), 4.65-4.59 (1H, m), 4.61(2H, s), 4.28 (2H, s), 3.78 (3H, s), 3.71 (3H, s), 3.49 (2H, s),2.96-2.84 (2H, m), 2.73-2.66 (2H, m), 2.59-2.54 (1H, dd), 1.07-1.05 (3H,d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 509, [M+Na]⁺ 531, [M−H]⁻ 507.

CHN analysis: Found: C, 66.69%; H, 7.44%; N, 5.14%.C₂₉H₃₆N₂O₆+0.2Et₂O+0.75H₂O requires C, 66.66%; H, 7.41%; N, 5.22%.

EXAMPLE 102-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-trifluoromethoxybenzyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-trifluoromethoxybenzyl)-acetamide(Preparation 10) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.32-7.30 (2H, d), 7.22-7.12 (5H, m), 7.08(1H, s), 7.03-7.01 (2H, d), 6.70-6.68 (1H, d), 4.62-4.59 (1H, m), 4.61(2H, s), 4.36 (2H, s), 3.51 (2H, s), 3.00-2.93 (1H, m), 2.90-2.85 (1H,dd), 2.73-2.69 (2H, m), 2.61-2.56 (1H, dd), 1.08-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 533, [M−H]⁻ 531.

CHN analysis: Found: C, 62.12%; H, 5.98%; N, 5.15%. C₂₈H₃₁F₃N₂O₅+0.5H₂Orequires C, 62.10%; H, 5.96%; N, 5.17%.

EXAMPLE 11 N-(2-Chloro,6-fluorobenzyl)-2-(3{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-chloro,6-fluorobenzyl)-acetamide (Preparation 11) using the method for example3 to give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.33-7.28 (1H, m), 7.25-7.22 (2H, m),7.18-7.15 (1H, t), 7.09-6.97 (5H, m), 6.70-6.68 (1H, d), 4.63-4.60 (1H,m), 4.61 (2H, s), 4.53 (2H, s), 3.45 (2H, s), 2.97-2.91 (1H, m),2.90-2.85 (1H, dd), 2.74-2.69 (2H, m), 2.57-2.52 (1H, dd), 1.06-1.05(3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 501/503, [M−H]⁻499/501.

CHN analysis: found: C, 62.90%; H, 6.06%; N, 5.34%; C₂₇H₃₀ClFN₂O₄+0.8H₂O requires C, 62.92%; H, 6.18%; N, 5.44%.

EXAMPLE 12N-(3,4-Dimethylbenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,4-dimethylbenzyl)-acetamide(Preparation 12) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.12 (3H, m), 7.07 (1H, s), 7.05-7.00(3H, m), 6.95-6.91 (2H, m), 6.70-6.68 (1H, d), 4.62-4.59 (1H, m), 4.61(2H, s), 4.26 (2H, s), 3.49 (2H, s), 2.98-2.90 (1H, m), 2.90-2.85 (1H,dd), 2.74-2.69 (2H, m), 2.60-2.55 (1H, dd), 2.20 (3H, s), 2.19 (3H, s),1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 477, [M−H]⁻475.

CHN analysis: found: C, 71.69; H, 7.70; N, 5.72; C₂₉H₃₆N₂O₄+0.5H₂Orequires C, 71.73%; H, 7.68%; N, 5.77%.

EXAMPLE 13N-[2-Fluoro-5-(trifluoromethyl)benzyl]-2-(3{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-[2-fluoro-5-(trifluoromethyl)benzyl]-acetamide(Preparation 13) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.61-7.57 (1H, m), 7.55-7.52 (1H, m),7.28-7.18 (3H, m), 7.14-7.12 (1H, m), 7.07 (1H, s), 7.03-7.01 (2H, d),6.70-6.68 (1H, d), 4.63-4.60 (1H, m), 4.61 (2H, s), 4.44 (2H, s), 3.52(2H, s), 3.00-2.93 (1H, m), m), 2.91-2.86 (1H, dd), 2.76-2.70 (2H, m),2.60-2.55 (1H, dd), 1.07-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 535, [M−H]⁻ 533.

CHN analysis: found: C, 62.26%; H, 5.81%; N, 5.09%; C₂₈H₃₀F₄N₂O₄+0.30H₂Orequires C, 62.28%; H, 5.71%; N, 5.19%.

EXAMPLE 14N-(2,6-Dichlorobenzyl)-2-(3{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2,6-dichlorobenzyl)-acetamide(Preparation 14) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.38-7.36 (2H, d), 7.27-6.97 (7H, m),6.70-6.68 (1H, d), 4.69-4.55 (5H, m), 3.46 (2H, s), 3.00-2.83 (2H, m),2.79-2.68 (2H, m), 2.61-2.50 (1H, m), 1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 517/519, [M+Na]⁺ 539/541, [M−H]⁻515/517.

CHN analysis: found: C, 61.40%; H, 6.13%; N, 5.15%; C₂₇H₃₀Cl₂N₂O₄+0.6H₂Orequires C, 61.39%; H, 5.95%; N, 5.30%.

EXAMPLE 152-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-phenylethyl)acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-phenylethyl)acetamide(Preparation 15) using the method for example 3 to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.49-7.30 (8H, m), 7.26-7.22 (3H, m),6.90-6.88 (1H, d), 4.81-4.78 (3H, m), 3.60-3.54 (4H, m), 3.16-3.00 (2H,m), 2.96-2.87 (4H, m), 2.80-2.75 (1H, dd), 1.28-1.26 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M−H]⁻461.

CHN analysis: found: C, 69.89%; H, 7.63%; N, 5.98%; C₂₈H₃₄N₂O₄+1.30H₂Orequires C, 69.20%; H, 7.59%; N, 5.76%.

EXAMPLE 16N-Benzyl-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared fromN-Benzyl-2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide(Preparation 16) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.29-7.18 (7H, m), 7.14-7.12 (1H, m), 7.08(1H, s), 7.05-6.99 (2H, m), 6.71-6.69 (1H, d), 4.64-4.62 (1H, m), 4.61(2H, s), 4.34 (2H, s), 3.51 (2H, s), 3.02-2.93 (1H, m), 2.91-2.86 (1H,m), 2.76-2.72 (2H, dd), 2.61-2.56 (1H, dd), 1.08-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 449, [M+Na]⁺ 471, [M−H]⁻447.

CHN analysis: found: C, 69.02%, H, 7.24%; N, 5.95%; C₂₇H₃₂N₂O₄+1.15H₂Orequires C, 69.11%; H, 7.37%; N, 5.97%.

EXAMPLE 17N-(3,5-Dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[teft-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,5-dichlorobenzyl)-acetamide(Preparation 17) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.28-7.13 (6H, m), 7.08 (1H, s), 7.04-7.01(2H, m), 6.71-6.69 (1H, d), 4.62 (2H, s), 4.62-4.59 (1H, m), 4.31 (2H,s), 3.52 (2H, s), s), 3.02-2.92 (1H, m), 2.90-2.85 (1H, m), 2.77-2.69(2H, m), 2.62-2.57 (1H, dd), 1.08-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 517/519, [M+Na]⁺ 539/541, [M−H]⁻515/517.

CHN analysis: found: C, 60.61%; H, 5.86%, N, 5.14%;C₂₇H₃₀Cl₂N₂O₄+0.95H₂O requires C, 60.67%; H, 6.01%; N, 5.24%.

EXAMPLE 18N-(4-Chlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-chlorobenzyl)-acetamide(Preparation 18) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.28-7.18 (6H, m), 7.13-7.11 (1H, m), 7.06(1H, s), 7.02-7.00 (2H, d), 6.70-6.68 (1H, d), 4.61 (2H, s), 4.61-4.58(1H, m), 4.32 (2H, s), 3.50 (2H, s), 2.95-2.90 (1H, m), 2.89-2.84 (1H,dd), 2.72-2.67 (2H, m), 2.60-2.55 (1H, dd), 1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 483/485, [M+Na]⁺ 505/507, [M−H]⁻481/483.

CHN analysis: found: C, 64.92%; H, 6.46%; N, 5.61%; C₂₇H₃₁ClN₂O₄+0.9H₂Orequires C, 64.96%; H, 6.62%; N, 5.61%.

EXAMPLE 194-{([2-(3-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoicacid

Prepared from4-{([2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoicacid (Preparation 19) using the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.86-7.84 (2H, d), 7.33 (1H, s), 7.28-7.09(7H, m), 6.78-6.76 (1H, d), 4.80 (1H, m, partially obscured by solvent),4.65 (2H, s), 4.38 (2H, s), 3.54 (2H, s), 3.43-3.36 (1H, m), 3.13-3.05(3H, m), 2.71-2.65 (1H, m), 1.16-1.14 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 493, [M+Na]⁺ 515, [M−H]⁻ 491.

EXAMPLE 202-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1R)-1-phenylethyl]acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1R)-1-phenylethyl]acetamide (Preparation 21) according to the method forexample 3 using dichloromethane:methanol: 880 ammonia (90:10:1 byvolume) as the column eluent to give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.27-7.01 (11H, m), 6.73-6.71 (1H, d),5.01-4.94 (1H, m), 4.69-4.63 (1H, m), 4.63 (2H, s), 3.49 (2H, s),3.09-3.01 (1H, m), 2.98-2.89 (1H, m), 2.85-2.76 (2H, m), 2.64-2.56 (1H,m), 1.44-1.42 (3H, d) 1.09-1.08 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M−H]⁻ 461.

CHN analysis: found: C, 69.24%; H, 7.35%; N, 5.73%; C₂₈H₃₄N₂O₄+1.30H₂Orequires C, 69.20%; H, 7.59%; N, 5.76%.

EXAMPLE 21 4-{(1R)-2-[((1R)-2-{3-[2-(3,4-Dihydroisoquinolin-2-(1H-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

Prepared from4-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[2-(3,4-dihydroisoquinolin-2-(1M-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol(Preparation 22) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.24-6.94 (10H, m), 6.70-6.68 (1H, d),4.69-4.67 (2H, m), 4.61 (2H, s), 4.61-4.58 (1H, m), 3.83-3.82 (2H, m),3.81-3.70 (2H, m), 2.95-2.80 (3H, m), 2.74-2.62 (3H, m), 2.60-2.46 (1H,m), 1.05-0.97 (3H, m) ppm.

LRMS (electrospray): m/z [M+H]⁺ 475, [M+Na]⁺ 497, [M−H]⁻473.

CHN analysis: found: C, 71.47%; H, 7.29%; N, 5.71%; C₂₉H₃₄N₂O₄+0.70H₂Orequires C, 71.49%; H, 7.32%; N, 5.75%.

EXAMPLE 22 4-{(1R)-2-[((1R)-2-{3-[2-(7-Ethoxy-6-methoxy-3,4-dihydroisoquinolin-2-(1H)-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

Prepared from4-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[2-(7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2-(1M-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol(Preparation 23) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.23-6.93 (6H, m), 6.70 (1H, s), 6.70-6.68(1H, d), 6.65-6.56 (1H, m), 4.61-4.57 (5H, m), 4.02-3.92 (2H, m), 3.82(2H, s), 3.76 -(3H, s), 3.82-3.67 (2H, m), 2.98-2.44 (7H, m), 1.38-1.33(3H, m), 1.06-0.96 (3H, m) ppm.

LRMS (electrospray): m/z [M+H]⁺ 549, [M+Na]⁺ 571, [M−H]⁻547.

CHN analysis: found: C, 68.60%; H, 7.47%; N, 4.96%; C₃₂H₄₀N₂O₆+0.70H₂Orequires C, 68.48%; H, 7.43%; N, 4.99%.

EXAMPLE 23N-[2-(4-Chlorophenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-(4-chlorophenyl)ethyl]acetamide(Preparation 24) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.22-7.16 (4H, m), 7.09-7.01 (6H, m),6.70-6.68 (1H, d), 4.62-4.59 (1H, m), 4.61 (2H, S), 3.39 (2H, S),3.39-3.35 (2H, t), 3.00-2.92 (1H, m), 2.90-2.85 (1H, dd), 2.75-2.68 (4H,m), 2.61-2.56 (1H, dd), 1.09-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 497, [M+Na]⁺ 519, [M−H]⁻ 495.

CHN analysis: found C, 66.68%; H, 6.77%; N, 5.66%; C₂₈H₃₃ClN₂O₄+0.40H₂Orequires C, 66.70%; H, 6.76%; N, 5.56%.

EXAMPLE 24N-[2-(4-Ethylphenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-(4-ethylphenyl)ethyl]acetamide(Preparation 25) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.22-7.16 (2H, m), 7.07-7.01 (8H, m),6.70-6.68 (1H, d), 4.64-4.60 (1H, m), 4.61 (2H, s), 3.41 (2H, s),3.37-3.34 (2H, t), 3.02-2.95 (1H, m), 2.91-2.86 (1H, dd), 2.75-2.68 (4H,m), 2.62-2.55 (3H, m), 1.20-1.16 (3H, t), 1.09-1.08 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 491, [M+Na]⁺ 513, [M−H]⁻489.

CHN analysis: found C: 71.77%; H, 7.84%; N, 5.58%; C₃₀H₃₈N₂O₄+0.60H₂Orequires C, 71.86%; H, 7.88%; N, 5.59%.

EXAMPLE 25N-(1,1-Dimethyl-2-phenylethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1,1-dimethyl-2-phenylethyl)acetamide(Preparation 26) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.24-7.20 (2H, m), 7.14-7.11 (4H, m),7.07-7.02 (3H, m), 6.97-6.95 (2H, m), 6.71-6.69 (1H, d), 4.65-4.61 (1H,m), 4.61 (2H, s), 3.38 (2H, s), 3.01-2.95 (1H, m), 2.99 (2H, s),2.92-2.87 (1H, dd), 2.79-2.73 (2H, m), 2.62-2.57 (1H, dd), 1.27 (3H, s),1.26 (3H, s), 1.08-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 491, [M+Na]⁺ 513, [M−H]⁻ 489.

CHN analysis: found: C, 71.96%; H, 7.81%; N, 5.51%. C₃₀H₃₈N₂O₄+0.60H₂Orequires C, 71.86%; H, 7.88%; N, 5.59%.

EXAMPLE 26N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide(Preparation 27) according to the method for example 3 to give the titlecompound as a white foam after trituration with ether.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.15 (2H, m), 7.06-7.00 (4H, m),6.82-6.77 (2H, m), 6.70-6.65 (2H, m), 4.64-4.59 (1H, m), 4.61 (2H, s),3.78 (3H, s), 3.75 (3H, S), 3.41 (2H, s), 3.40-3.37 (2H, t), 2.98-2.91(1H, m), 2.90-2.85 (1H, dd), 2.74-2.67 (4H, m), 2.60-2.55 (1H, dd),1.08-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 523, [M+Na]⁺ 545, [M−H]⁻ 521.

CHN analysis: found: C, 67.27%; H, 7.73%; N, 4.96%.C₃₀H₃₈N₂O₆+0.70H₂O+0.20Et₂O requires C, 67.25%; H, 7.59%; N, 5.09%.

EXAMPLE 27N-(3,4-Difluorobenzyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3,4-difluorobenzyl)acetamide(Preparation 28) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.15 (3H, m), 7.13-7.08 (3H, m),7.06-7.00 (3H, m), 6.70-6.68 (1H, d), 4.61-4.57 (3H, m), 4.30 (2H, s),3.50 (2H, s), 2.94-2.83 (2H, m), 2.71-2.66 (2H, m), 2.59-2.54 (1H, dd),1.06-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 485, [M+Na]⁺ 507, [M−H]⁻ 483.

CHN analysis: found: C, 65.60%; H, 6.32%; N, 5.76%. C₂₇H₃₀F₂N₂O₄+0.50H₂Orequires C, 65.71%; H, 6.33%; N, 5.68%.

EXAMPLE 284-{(1R)-2-[((1R)-2-{3-[2-(1,3-Dihydro-2H-isoindol-2-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

Prepared from4-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol(Preparation 29) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.29-7.27 (4H, m), 7.23-7.19 (2H, m),7.15-7.13 (1H, d), 7.09 (1H, s), 7.02-6.96 (2H, m), 6.68-6.66 (1H, d),4.74 (2H, s), 4.61-4.58 (3H, m), 3.77 (2H, s), 3.29 (2H, s), 2.96-2.83(2H, m), 2.71-2.65 (2H, m), 2.62-2.57 (1H, dd), 1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 461, [M−H]⁻ 459.

EXAMPLE 292-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylacetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylacetamide(Preparation 30) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.53-7.51 (2H, d), 7.29-7.10 (6H, m),7.08-6.99 (3H, m), 6.70-6.68 (1H, d), 4.66-4.58 (3H, m), 3.62 (2H, s),3.01-2.85 (2H, m), 2.74-2.68 (2H, m), 2.62-2.57 (1H, dd), 1.08-1.06 (3H,d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 435, [M+Na]⁺ 457, [M−H]⁻ 433.

EXAMPLE 302-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1-naphthylmethyl)acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1-naphthylmethyl)acetamide(Preparation 31) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.96-7.94 (1H, d), 7.86-7.83 ((1H, d),7.79-7.76 (1H, dd), 7.48-7.42 (2H, m), 7.40-7.36 (2H, m), 7.20-7.09 (3H,m), 7.00-6.96 (3H, m), 6.70-6.68 (2H, d), 4.80 (2H, s), 4.61-4.55 (3H,m), 3.49 (2H, s), 2.83-2.78 (2H, m), 2.66-2.60 (2H, m), 2.50-2.45 (1H,dd), 1.00-0.99 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 499, [M+Na]⁺ 521, [M−H]⁻ 497.

EXAMPLE 31N-(3,4-Dichlorobenzyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide

Prepared from(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine, using the amidecoupling procedure of preparation 5 and the deprotection procedure ofexample 3 to give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.44-7.36 (2H, m), 7.23-7.13 (2H, m),7.10-7.04 (2H, m), 7.02-6.93 (3H, m), 6.70-6.67 (1H, d), 4.69-4.61 (5H,m), 3.78-3.76 (2H, d), 2.96 (2H, s), 2.93-2.83 (3H, m), 2.69-2.63 (2H,m), 2.60-2.49 (1H, m), 1.07-1.00 (3H, m) ppm.

LRMS (electrospray): m/z [M+H]⁺ 531, [M+Na]⁺ 553, [M−H]⁻ 529.

EXAMPLE 322-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-pyridin-2-ylethyl)acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-pyridin-2-ylethyl)acetamide(Preparation 32) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=8.40-8.39 (1H, d), 7.69-7.65 (1H, m),7.24-7.76 (4H, m), 7.06-7.00 (4H, m), 6.70-6.68 (1H, d), 4.61-4.59 (3H,m), 3.53-3.50 (2H, t), 3.40 (2H, s), 2.96-2.84 (4H, m), 2.72-2.66 (2H,m), 2.60-2.55 (1H, m), 1.08-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 464, [M+Na]⁺ 486, [M−H]⁻ 462.

CHN analysis: found: C, 67.36%; H, 7.21%; N, 8.95%. C₂₇H₃₃N₃O₄+1.00H₂Orequires C, 67.34%; H, 7.33%; N, 8.73%.

EXAMPLE 332-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(2R)-2-phenylpropyl]acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(2R)-2-phenylpropyl]acetamide(Preparation 33) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.31-7.21 (4H, m), 7.18-7.12 (3H, m),7.03-6.97 (4H, m), 6.70-6.68 (1H, d), 4.61-4.57 ((3H, m), 3.37 (2H, s),2.93-2.79 (4H, m), 2.71-2.64 (2H, m), 2.57-2.52 (1H, m), 1.26-1.24 (1H,m), 1.20-1.18 (3H, d), 1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 477, [M+Na]⁺ 499, [M−H]⁻ 475.

CHN analysis: found: C, 71.73%; H, 7.75%; N, 6.12%. C₂₉H₃₆N₂O₄+0.50H₂Orequires C, 71.73%; H, 7.68%; N, 5.77%.

EXAMPLE 34N-Benzyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide

Prepared fromN-benzyl-2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide(Preparation 34) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.33-7.17 (6H, m), 7.11-7.06 (2H, m),7.03-7.00 (3H, m), 6.71-6.69 (1H, d), 4.62-4.53 (5H, m), 3.78-3.76 (2H,m), 2.96-2.84 (5H, m), 2.75-2.67 (2H, m), 2.60-2.52 (1H, m), 1.03 (3H,m) ppm.

LRMS (electrospray): m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M−H]⁻ 461.

CHN analysis: found: C, 70.58%; H, 7.38%; N, 5.78%. C₂₈H₃₄N₂O₄+0.75H₂Orequires C, 70.64%; H, 7.52%; N, 5.88%.

EXAMPLE 35N-[3-(4-Fluorophenyl)propyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[3-(4-fluorophenyl)propyl]acetamide(Preparation 35) according to the method for example 3 to give the titlecompound as a white foam.

¹HNMR (400 MHz, CD₃OD) δ: 7.25-7.22 (2H, m), 7.17-7.12 (4H, m),7.06-6.96 (4H, m), 6.74 (1H, d), 4.67-4.62 (m, 3H), 3.49 (2H, s),3.22-3.19 (2H, s), 2.99-2.87 (2H, m), 2.75-2.70 (2H, m), 2.63-2.57 (3H,m), 1.81-1.76 (2H, m), 1.09(3H, s) ppm.

MS (electrospray): 495 [M+H]⁺ , 517 [M+Na]⁺ , 493 [M−H]⁻

EXAMPLE 36N-(2,6-Dichlorobenzyl)-3-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanamide

Prepared from2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2,6-dichlorobenzyl)-propanamide(Preparation 45) using the method for example 3 to give the titlecompounds as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.39-7.37 (2H, d), 7.28-7.22 (2H, m),7.15-7.11 (1H, t), 7.03-7.01 (2H, d), 6.98 (1H, s), 6.95-6.93 (1H, d),6.71-6.69 (1H, d), 4.66-4.58 (5H, m), 3.05-2.09 (1H, m), 2.94-2.84 (3H,m), 2.79-2.71 (2H, m), 2.60-2.54 (1H, dd), 2.48-2.41 (2H, t), 1.09-1.08(3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 531/533, [M+Na]⁺ 553/555, [M−H]⁻529/531.

CHN analysis: found: C, 60.34%; H, 6.00%; N, 4.89%.C₂₈H₃₂Cl₂N₂O₄+1.45H₂O requires C, 60.31%; H, 6.31%; N, 5.02%.

EXAMPLE 37N-(2,6-Dimethoxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propananmide

Prepared from3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2,6-dimethoxybenzyl)propanamide(Preparation 46) according to the method for example 1 usingmethanol:water (2.4:1 v/v) instead of acetic acid as solvent and usingdichloromethane:methanol: 880 ammonia (97.5:2.5:0.25 by volume) as thecolumn eluent to give the title compound as a white solid aftertrituration with diethyl ether.

¹H NMR (400 MHz, CD₃OD): δ=7.24-7.19 (2H, m), 7.13-7.09 (1H, t),7.01-6.99 (2H, d), 6.95-6.90 (2H, m), 6.70-6.68 (1H, d), 6.61-6.59 (2H,d), 4.65-4.60 (1H, m), 4.60 (2H, s), 4.38 (2H, s), 3.78 (6H, s),2.97-2.81 (4H, m), 2.73-2.64 (2H, m), 2.57-2.52 (1H, dd), 2.43-2.39 (2H,t), 1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 523, [M+Na]⁺ 545, [M−H]⁻ 521.

EXAMPLE 38N-(2-Ethoxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared from3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-ethoxybenzyl)propanamide(Preparation 47) according to the method for example 1 usingmethanol:water (2.4:1 v/v) instead of acetic acid as solvent and usingdichloromethane:methanol: 880 ammonia (94:6:0.6 by volume) as the columneluent to give the title compound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.24 (1H, s), 7.19-7.15 (2H, t), 7.07-6.98(4H, m), 6.93-6.87 (2H, dd), 6.81-6.77 (1H, t), 6.72-6.70 (1H, d),4.70-4.64 (1H, m), 4.62 (2H, s), 4.31 (2H, s), 4.05-4.00 (2H, q),3.10-3.04 (1H, m), 2.97-2.88 (3H, m), 2.83-2.74 (2H, m), 2.62-2.50 (3H,m), 1.39-1.36 (3H, t), 1.09-1.08 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 507, [M+Na]⁺ 529, [M−H]⁻ 505.

CHN analysis: found: C, 69.31%; H, 7.53%; N, 5.20%. C₃₀H₃₈N₂O₅+0.75H₂Orequires C, 69.27%; H, 7.65%; N, 5.39%.

EXAMPLE 39N-(3,4-Dimethylbenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared from3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3,4-dimethylbenzyl)propanamide(Preparation 48) according to the method for example 1 usingmethanol:water (2.4:1 v/v) instead of acetic acid as solvent and usingdichloromethane:methanol: 880 ammonia (94:6:0.6 by volume) as the columneluent to give the title compound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.21 (1H, s), 7.16-7.12 (1H, t), 7.04-6.92(6H, m), 6.82-6.81 (1H, d), 6.70-6.68 (1H, d), 4.65-4.61 (1H, m), 4.61(2H, s), 4.22 (2H, s), 2.97-2.85 (4H, m), 2.72-2.64 (2H, m), 2.57-2.52(1H, dd), 2.51-2.47 (2H, t), 2.20 (6H, s), 1.06-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 491, [M+Na]⁺ 513, [M−H]⁻ 489.

CHN analysis: Found: C, 71.55%; H, 7.71%; N, 5.59%. C₃₀H₃₈N₂O₄+0.70H₂Orequires C, 71.60%; H, 7.89%; N, 5.57%.

EXAMPLE 40N-(2,3-Dihydro-1H-inden-2-yl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared from3-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2,3-dihydro-1H-inden-2-yl)propanamide(Preparation 49) according to the method for example 1 usingmethanol:water (2.4:1 v/v) instead of acetic acid as solvent and usingdichloromethane:methanol: 880 ammonia (94:6:0.6 by volume) as the columneluent to give the title compound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.09 (6H, m), 7.02-6.92 (4H, m),6.69-6.67 (1H, d), 4.65-4.56 (1H, m), 4.60 (2H, s), 4.53-4.50 (1H, t),3.20-3.14 (2H, dd), 2.94-2.81 (4H, m), 2.76-2.64 (4H, m), 2.57-2.52 (1H,dd), 2.43-2.40 (2H, t), 1.06-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 489, [M+Na]⁺ 511, [M−H]⁻ 487.

CHN analysis: Found: C, 71.08%; H, 7.35%; N, 5.58%. C₃₀H₃₆N₂O₄+1.05H₂Orequires C, 71.00%; H, 7.57%; N, 5.52%.

EXAMPLE 414-{(1R)-2-[((1R)-2-{3-[3-(3,4-Dihydroisoquinolin-2-(1H)-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

Prepared from4-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[3-(3,4-dihydroisoquinolin-2-(1H)-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol(Preparation 50) according to the method for example 1 usingmethanol:water (2.4:1 v/v) instead of acetic acid as solvent and usingdichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) as the columneluent to give the title compound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.22 (1H, s), 7.16-6.93 (8H, m), 6.87-6.85(1H, bd), 6.71-6.68 (1H, m), 4.65-4.55 (2H, m), 4.63-4.60 (1H, m), 4.61(2H, s), 3.75-3.60 (2H, m), 2.95-2.85 (4H, m), 2.80-2.60 (6H, m),2.53-2.47 (1H, dd), 1.05-1.02 (3H, m) ppm.

LRMS (electrospray): m/z [M+H]⁺ 489, [M+Na]⁺ 511, [M−H]⁻ 487.

CHN analysis: Found: C, 71.06%; H, 7.27%; N, 5.46%. C₃₀H₃₆N₂O₄+1.05H₂Orequires C, 71.00%; H, 7.57%; N, 5.52%.

EXAMPLE 42N-(2-Chloro-6-fluorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

A solution of3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) (150 mg, 0.29 mmol),O-(1H-benzotrizol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(133 mg, 0.35 mmol), 2-fluoro-6-chlorobenzylamine (56 mg, 0.35 mmol) andtriethylamine (0.12 ml, 0.88 mmol) were stirred at room temperature for16 hours in N,N-dimethylformamide (3 ml). The solvent was removed invacuo and the resulting brown oil was purified by flash columnchromatography on silica gel eluting with dichloromethane:methanol:880ammonia (98:2:0.2 followed by 94:6:0.6 by volume) to give the titlecompound as a white foam (30 mg).

¹H NMR (400 MHz, CD₃OD): δ=7.32-7.20 (3H, m), 7.12-6.98 (4H, m), 6.95(1H, s), 6.92-6.90 (1H, d), 6.70-6.68 (1H, d), 4.64-4.60 (3H, m), 4.49(2H, s), 2.98-2.83 (4H, m), 2.75-2.66 (2H, m), 2.58-2.53 (1H, dd),2.47-2.43 (2H, t), 1.08-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 517, [M+Na]⁺ 537, [M−H]⁻ 513.

CHN analysis: Found: C, 62.04%; H, 6.11%; N, 5.15%.C₂₈H₃₂N₂O₄ClF+0.05H₂O+0.40CH₂Cl₂ requires C, 62.03%; H, 6.03%; N, 5.09%.

EXAMPLE 43N-(2-Chlorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.35-7.01 (10H, m), 6.76-6.74 (1H, d),4.77-4.74 (1H, dd), 4.64 (2H, s), 4.39 (2H, s), 3.07-2.90 (6H, m),2.67-2.55 (3H, m), 1.14-1.13 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 497, [M+Na]⁺ 519, [M−H]⁻ 495.

EXAMPLE 443-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(pyridin-2-ylmethyl)propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=8.42-8.41 (1H, d), 7.71-7.67 (1H, m),7.27-7.14 (3H, m), 7.06-6.96 (5H, m), 6.71-6.68 (1H, d), 4.63-4.59 (3H,m), 4.42 (2H, s), 2.96-2.85 (4H, m), 2.72-2.65 (2H, m), 2.59-2.53 (3H,m), 1.06-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 464, [M+Na]⁺ 486, [M−H]⁻ 462.

CHN analysis: Found: C, 66.60%; H, 6.97%; N, 8.54%.C₂₇H₃₃N₃O₄+0.05H₂O+0.35CH₂Cl₂ requires C, 66.47%; H, 6.89%; N, 8.50%.

EXAMPLE 45N-Benzyl-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.26-6.90 (11H, m), 6.70-6.68 (1H, d),4.61-4.58 (3H, m), 4.30 (2H, s), 2.94-2.83 (4H, m), 2.70-2.63 (2H, m),2.57-2.49 (3H, m), 1.06-1.04 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M−H]⁻ 461.

CHN analysis: found: C, 68.16%; H, 7.16%; N, 5.66%.C₂₈H₃₄N₂O₄+0.05H₂O+0.25CH₂Cl₂ requires C, 68.11%; H, 7.03%; N, 5.58%.

EXAMPLE 463-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.26-7.22 (3H, m), 7.18-7.12 (4H, m),7.03-7.01 (2H, d), 6.97-6.94 (2H, d), 6.71-6.69 (1H, d), 4.64-4.58 (3H,m), 3.36-3.30 (2H, m), 3.00-2.81 (4H, m), 2.75-2.68 (4H, m), 2.59-2.54(1H, dd), 2.42-2.39 (2H, t), 1.08-1.06 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 477, [M+Na]⁺ 499, [M−H]⁻ 475.

EXAMPLE 473-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3-phenylpropyl)propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.25-7.21 (3H, m), 7.15-7.11 (4H, m),7.04-7.00 (2H, m), 6.97 (1H, s), 6.92-6.91 (1H, d), 6.71-6.69 (1H, d),4.62-4.58 (3H, m), 3.14-3.11 (2H, t), 2.93-2.83 (4H, m), 2.70-2.62 (2H,m), 2.54-2.49 (3H, m), 2.45-2.42 (2H, t), 1.73-1.66 (2H, m), 1.04-1.03(3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 491, [M+Na]⁺ 513, [M−H]⁻ 489.

EXAMPLE 484-{(1R)-2-[((1R)-2-{3-[3-(1,3-Dihydro-2H-isoindol-2-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a pale grey foam.

¹H NMR (400 MHz, CD₃OD): δ=7.30-7.21 (5H, m), 7.17-7.13 (1H, t),7.10-7.08 (1H, d), 7.03-6.99 (2H, m), 6.93-6.92 (1H, d), 6.70-6.68 (1H,d), 4.71-4.69 (4H, d), 4.65-4.58 (3H, m), 2.97-2.84 (4H, m), 2.74-2.65(4H, m), 2.56-2.51 (1H, dd), 1.02-1.01 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 475, [M+Na]⁺ 497, [M−H]⁻ 473.

CHN analysis: found: C, 70.10%; H, 7.03%; N, 5.66%. C₂₉H₃₄N₂O₄+1.20H₂Orequires C, 70.19%; H, 7.39%; N, 5.65%.

EXAMPLE 49N-[2-Fluoro-5-(trifluoromethyl)benzyl]-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.63-7.59 (2H, m), 7.28-7.21 (2H, m),7.12-7.08 (1H, m), 7.02-6.91 (4H, m), 6.70-6.68 (1H, d), 4.63-4.58 (3H,m), 4.40 (2H, s), 2.96-2.84 (4H, m), 2.72-2.64 (2H, m), 2.57-2.48 (3H,m), 1.06-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 549, [M+Na]⁺ 571, [M−H]⁻ 547.

CHN analysis: Found: C, 60.76%; H, 5.79%; N, 4.87%. C₂₉H₃₂N₂O₄F₄+1.35H₂Orequires C, 60.80%; H, 6.11%; N, 4.89%.

EXAMPLE 50N-(2-Hydroxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide

Prepared according to the procedure used for example 42 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.21 (1H, m), 7.12-6.99 (4H, m), 6.95-6.91(3H, m), 6.77-6.68 (3H, m), 4.65-4.59 (3H, m), 4.27 (2H, s), 2.94-2.84(4H, m), 2.70-2.61 (2H, m), 2.55-2.47 (3H, m), 1.05-1.04 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 479, [M+Na]⁺ 501, [M−H]⁻ 477.

CHN analysis: Found: C, 66.61%; H, 6.91%; N, 5.57%. C₂₈H₃₄N₂O₅+0.40CH₂Cl₂ requires C, 66.55%; H, 6.84%; N, 5.47%.

EXAMPLE 513-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-phenylpropanamide

Prepared according to the procedure used for preparation 1 using3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid (Preparation 60) and the appropriate amine, substitutingdichloromethane instead of ethyl acetate as the extraction solvent togive the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.49-7.47 (2H, d), 7.28-7.21 (3H, m),7.17-7.13 (1H, t), 7.08-7.00 (4H, m), 6.94-6.92 (1H, d), 6.71-6.69 (1H,d), 4.63-4.58 (3H, m), 2.97-2.84 (4H, m), 2.71-2.52 (5H, m), 1.04-1.02(3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 449, [M+Na]⁺ 471, [M−H]⁻ 447.

EXAMPLES 52-63

Examples 52 to 63 are of formula:

A solution of(4-{2-[2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]propyl}phenyl)aceticacid (Preparation 61) (150 mg, 0.32 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.34mmol), 1-hydroxybenzotriazole monohydrate (54 mg, 0.34 mol) anddiisopropylethylamine (82 mg, 0.63 mmol) were stirred inN,N-dimethylformamide (3 ml) with the appropriate amine (0.34 mmol) atroom temperature for 18 hours. The solvent was removed in vacuo and thecrude material taken up in a mixture of dichloromethane (5 ml) andsaturated potassium carbonate (3 ml) and passed through a phaseseparating column. The organic layer was concentrated in vacuo and thematerial taken up in methanol (1 ml) and treated with ammonium fluoride(117 mg, 3.20 mmol) in water (0.5 ml) and the resulting mixture heatedto 40° C. for 20 hours

The solvent was removed in vacuo and dimethylsulfoxide (2 ml) added andthe mixture filtered before being purified by reverse phasechromatography (A—acetonitrile, B—H₂O buffered with 0.1% diethylamine:0-1.90 min 5% B, 1.90-2.00 min 5-10% B, 2.00-10.50 min 10-95% B,10.50-13.80 min 95% B) using a 150×21.2 mm C8(2) column (0-3.00 min10-95% B).

Amine used HRMS HRMS Example (intermediate [M + H]⁺ [M + H]⁺ Retentionnumber Name (3), (3′) or (3″)) calculated found minutes 52N-Benzyl-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)acetamide

449.2442 449.2471 1.64 532-(4-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)-N-(3-phenyl-propyl)acetamide

477.2755 477.2730 1.86 542-(4-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)-N-indan-2-yl-acetamide

475.2598 475.2574 1.81 551-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)ethanone

475.2598 475.2572 1.86 56N-(2-Hydroxybenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide

483.2052 483.2029 1.79 57N-(3-Chlorobenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide

483.2052 483.2028 1.83 58N-(4-Chlorobenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide

483.2052 483.2028 1.83 592-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(2-methoxybenzyl)-acetamide

479.2547 479.2522 1.74 602-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)-N-(3-methoxybenzyl)acetamide

479.2547 479.2523 1.68 612-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(4-methoxybenzyl)-acetamide

479.2547 479.2524 1.66 62N-(2,6-Dimethoxybenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxy-methylphenyl)-ethylamino]propyl}phenyl)-acetamide

509.2653 509.2627 1.79 632-(4-{(2R)-2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethyl-amino]propyl}phenyl)-N-(pyridin-2-ylmethyl)acetamide

450.2394 450.2375 1.38

EXAMPLE 64N-[2-Fluoro-5-(trifluoromethyl)benzyl]-2-{4-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

Prepared from2-{4-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-fluoro-5-(trifluoromethyl)benzyl]acetamide(Preparation 67) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.61-7.53 (2H, m), 7.35-6.98 (7H, m), 6.65(1H, d), 4.60 (3H, m), 4.46 (2H, s), 3.55 (2H, s), 3.00-2.90 (2H, m),2.75 (2H, m), 2.60 (1H, m), 1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 535, [M+Na]⁺ 557, [M−H]⁻ 533.

EXAMPLE 652-{4-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)acetamide

Prepared from2-{4-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)acetamide(Preparation 68) according to the method for example 3 to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.26-7.00 (11H, m), 6.69 (1H, d), 4.60 (3H,m), 3.40 (4H, m), 2.98 (2H, m), 2.70 (4H, m), 2.58 (1H, m), 1.07 (3H, d)ppm.

LRMS (electrospray): m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M−H]⁻ 461.

Preparation 1:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2,6-dimethoxybenzyl)-acetamide

A solution of(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) (150 mg, 0.32 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35mmol), hydroxybenzotriazole monohydrate (47 mg, 0.35 mmol) inN,N-dimethylformamide (3 ml) was treated with triethylamine (0.09 ml,0.63 mmol) and 2,6-dimethoxybenzylamine (58 mg, 0.35 mmol) and theresulting suspension left to stir at room temperature under a nitrogenatmosphere for 18 hours. The solvent was removed in vacuo and theresidue partitioned between ethyl acetate (10 ml) and saturated aqueoussodium bicarbonate (10 ml). The organic phase was separated, and theaqueous phase extracted with further ethyl acetate (2×10 ml). Thecombined organic extracts were washed with water (5 ml), brine (5 ml),dried (sodium sulphate) and the solvent removed in vacuo. The residuewas purified by flash column chromatography on silica gel eluting withdichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give thetitle compound as a pale yellow oil (128 mg).

¹H NMR (400 MHz, CD₃OD): δ=7.23-7.14 (3H, m), 7.09-7.07 (1H, d),6.99-6.93 (3H, m), 6.69-6.67 (1H, d), 6.59-6.61 (2H, d), 4.70-4.67 (1H,m), 4.61 (2H, d), 4.41 (2H, s), 3.75 (6H, s), 3.42 (2H, s), 2.89-2.81(2H, m), 2.67-2.60 (2H, m), 2.53-2.48 (1H, dd), 1.02-1.01 (3H, d), 0.84(9H, s), 0.00 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 623, [M+Na]⁺ 645, [M−H]⁻ 621.

Preparation 2:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-ethoxybenzyl)-acetamide

Prepared according to the procedure used for preparation 1 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.17 (3H, m), 7.14-7.12 (2H, d), 7.04(1H, s), 7.00-6.98 (2H, d), 6.91-6.89 (1H, d), 6.85-6.81 (1H, t),6.70-6.68 (1H, d), 4.72-4.68 (1H, t), 4.62-4.61 (2H, d), 4.35 (2H, s),4.04-3.98 (2H, q), 3.50 (2H, s), 2.94-2.84 (2H, m), 2.72-2.62 (2H, m),2.56-2.51 (1H, dd), 1.34-1.30 (3H, t), 1.04-1.02 (3H, d), 0.84 (9H, s),0.00 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 607, [M+Na]⁺ 629, [M−H]⁻ 605.

Preparation 3:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-hydroxybenzyl)-acetamide

Prepared according to the procedure used for preparation 1 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine, substitutingdichloromethane as the reaction solvent to give the title compound as awhite solid.

¹H NMR (400 MHz, CD₃OD): δ=7.19-7.02 (6H, m), 6.99-6.95 (2H, m),6.75-6.70 (2H, m), 6.68-6.66 (1H, d), 4.71-4.67 (1H, t), 4.61 (2H, d),4.32 (2H, s), 3.49 (2H, s), 2.91-2.84 (2H, m), 2.70-2.61 (2H, m),2.55-2.50 (1H, dd), 1.04-1.03 (3H, d), 0.84 (9H, s), 0.01 (3H, s), −0.18(3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 579, [M+Na]⁺ 601, [M−H]⁻ 577.

Preparation 4:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-indan-2-yl-acetamide

Prepared according to the procedure used for preparation 3 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.20-7.09 (7H, m), 7.02 (1H, s), 6.99-6.96(2H, t), 6.69-6.67 (1H, d), 4.71-4.68 (1H, m), 4.61-4.60 (2H, d),4.564.52 (1H, t) 3.42 (2H, s), 3.26-3.20 (2H, dd), 2.92-2.79 (4H, m),2.69-2.62 (2H, m), 2.56-2.51 (1H, m), 1.05-1.03 (3H, d), 0.83 (9H, s),0.00 (3H, s), −0.20 (3H, s), ppm.

LRMS (electrospray): m/z [M+H]⁺ 589, [M+Na]⁺ 611, [M−H]⁻ 587.

Preparation 5:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,4-dichlorobenzyl)-acetamide

Prepared according to the procedure used for preparation 1 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine substitutingdichloromethane instead of ethyl acetate as the extraction solvent togive the title compound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.41-7.39 (1H, d), 7.34 (1H, s), 7.20-7.16(2H, m), 7.14-7.10 (2H, t), 7.03 (1H, s), 7.00-6.96 (2H, d), 6.68-6.66(1H, d), 4.70-4.67 (1H, t), 4.61-4.60 (2H, d), 4.30 (2H, s), 3.49 (2H,s), 2.92-2.84 (2H, m), 2.70-2.60 (2H, m), 2.56-2.51 (1H, dd), 1.03-1.01(3H, d), 0.82 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 631/633, [M+Na]⁺ 653/655, [M−H]⁻629/631.

Preparation 6:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-[4-(aminosulfonyl)benzyl]-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.82-7.79 (2H, d), 7.38-7.36 (2H, d),7.22-7.13 (3H, m), 7.05 (1H, s), 7.01-6.99 (2H, d), 6.70-6.67 (1H, d),4.72-4.69 (1H, t), 4.62-4.61 (2H, d), 4.42 (2H, s), 3.51 (2H, s),2.95-2.84 (2H, m), 2.71-2.63 (2H, m), 2.57-2.52 (1H, dd), 1.05-1.03 (3H,d), 0.83 (9H, s), 0.00 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 642, [M+Na]⁺ 664, [M−H]⁻ 640.

Preparation 7:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(pyridin-2-ylmethyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=8.44-8.42 (1H, d), 7.74-7.70 (1H, t),7.27-7.23 (2H, m), 7.20-7.13 (3H, m), 7.06 (1H, s), 6.99-6.97 (2H, m),6.68-6.66 (1H, d), 4.71-4.67 (1H, t), 4.61 (2H, d), 4.46 (2H, s), 3.55(2H, s), 2.93-2.85 (2H, m), 2.71-2.63 (2H, m), 2.58-2.53 (1H, dd),1.06-1.04 (3H, d), 0.84 (9H, s), 0.01 (3H, s), −0.18 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 564, [M+Na]⁺ 586, [M−H]⁻ 562.

Preparation 8:4-{(2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetylamino)-methyl}-benzamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.79-7.77 (2H, d), 7.31-7.28 (2H, d),7.20-7.11 (3H, m), 7.04 (1H, s), 6.99-6.97 (2H, m), 6.68-6.66 (1H, d),4.71-4.69 (1H, t), 4.61-4.60 (2H, d), 4.40 (2H, s), 3.51 (2H, s),2.92-2.83 (2H, m), 2.70-2.61 (2H, m), 2.58-2.53 (1H, m), 1.06-1.04 (3H,d), 0.83 (9H, s), 0.00 (3H, s), −0.18 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 606, [M+Na]⁺ 628, [M−H]⁻ 604.

Preparation 9:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,4-dimethoxybenzyl)-acetamide

Prepared according to the procedure used for preparation 1 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.20-7.13 (3H, m), 7.05 (1H, s), 7.00-6.98(2H, d), 6.86-6.84 (1H, d), 6.79-6.77 (2H, m), 6.70-6.68 (1H, d),4.72-4.68 (1H, m), 4.62-4.61 (2H, d), 4.29 (2H, s), 3.78 (3H, s), 3.71(3H, s), 3.48 (2H, s), 2.94-2.83 (2H, m), 2.70-2.60 (2H, m), 2.57-2.51(1H, m), 1.04-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.19 (3H, s)ppm.

LRMS (electrospray): m/z [M+H]⁺ 623, [M+Na]⁺ 645, [M−H]⁻ 621.

Preparation 10:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-trifluoromethoxybenzyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.32-7.30 (2H, d), 7.21-7.12 (5H, m), 7.05(1H, s), 7.00-6.97 (2H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t), 4.60(2H, d), 4.36 (2H, s), 3.49 (2H, s), 2.93-2.85 (2H, m), 2.70-2.60 (2H,m), 2.57-2.52 (1H, dd), 1.04-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s),−0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 647, [M−H]⁻ 645.

Preparation 11:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-chloro,6-fluorobenzyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.33-7.14 (4H, m), 7.10-7.06 (2H, m),7.02-6.95 (3H, m), 6.69-6.67 (1H, d), 4.72-4.68 (1H, t), 4.61-4.60 (2H,s), 4.52 (2H, s), 3.44 (2H, s), 2.93-2.85 (2H, m), 2.71-2.61 (2H, m),2.54-2.49 (1H, dd), 1.04-1.02 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.19(3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 615/617, [M+Na]⁺ 637/639, [M−H]⁻613/615.

Preparation 12:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,4-dimethylbenzyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.19-7.11 (3H, m), 7.04-6.90 (6H, m),6.68-6.66 (1H, d), 4.70-4.67 (1H, t), 4.61-4.60 (2H, d), 4.26 (2H, s),3.47 (2H, s), 2.91-2.84 (2H, m), 2.69-2.60 (2H, m), 2.55-2.50 (1H, dd),2.20 (3H, s), 2.18 (3H, s), 1.03-1.02 (3H, d), 0.82 (9H, s), −0.01 (3H,s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 591, [M−H]⁻ 589.

Preparation 13:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-[2-fluoro-5-(trifluoromethyl)benzyl]-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.61-7.58 (1H, m), 7.55-7.53 (1H, d),7.28-7.12 (4H, m), 7.05 (1H, s), 7.02-6.97 (2H, m), 6.69-6.67 (1H, d),4.72-4.69 (1H, t), 4.61 (2H, d), 4.45 (2H, s), 3.51 (2H, s), 2.93-2.84(2H, m), 2.74-2.60 (2H, m), 2.57-2.51 (1H, dd), 1.04-1.03 (3H, d), 0.83(9H, s), 0.00 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 649, [M−H]⁻ 647.

Preparation 14:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2,6-dichlorobenzyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.35-7.33 (2H, m), 7.25-7.21 (1H, m), 7.17(1H, s), 7.14-7.10 (1H, m), 7.07-7.05 (1H, m), 7.00 (1H, s), 6.97-6.91(2H, m), 6.66-6.64 (1H, d), 4.68-4.65 (1H, t), 4.61 (2H, s), 4.58-4.57(2H, d), 3.42 (2H, s), 2.89-2.82 (2H, m), 2.67-2.60 (2H, m), 2.51-2.47(1H, dd), 1.00-0.99 (3H, d), 0.80 (9H, s), −0.04 (3H, s), −0.23 (3H, s)ppm.

LRMS (electrospray): m/z [M+H]⁺ 631/633, [M+Na]⁺ 653/655, [M−H]⁻629/631.

Preparation 15:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-phenylethyl)acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a brown oil.

¹H NMR (400 MHz, CD₃OD): δ=7.31-7.11 (7H, m), 7.07-7.05 (1H, d),6.99-6.97 (3H, m), 6.68-6.66 (1H, d), 4.70-4.67 (1H, t), 4.61-4.60 (2H,d), 3.41-3.37 (2H, m), 3.34 (2H, s), 2.95-2.84 (2H, m), 2.81-2.73 (2H,m), 2.68-2.61 (2H, m), 2.56-2.51 (1H, dd), 1.05-1.03 (3H, d), 0.82 (9H,s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 577, [M+Na]⁺ 599, [M−H]⁻ 575.

Preparation 16:N-Benzyl-2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.35-7.12 (8H, m), 7.04 (1H, s), 6.99-6.97(2H, d), 6.69-6.67 (1H, d), 4.70-4.67 (1H, t), 4.61-4.60 (2H, d), 4.35(2H, s), 3.49 (2H, s), 2.90-2.83 (2H, m), 2.69-2.61 (2H, m), 2.55-2.50(1H, dd), 1.04-1.02 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.20 (3H, s)ppm.

LRMS (electrospray): m/z [M+Na]⁺ 585, [M−H]⁻ 561.

Preparation 17:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(3,5-dichlorobenzyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.33-7.28 (2H, m), 7.22-7.12 (4H, m), 7.05(1H, s), 7.01-6.98 (2H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t),4.62-4.61 (2H, d), 4.32 (2H, s), 3.51 (2H, s), 2.91-2.84 (2H, m),2.71-2.61 (2H, m), 2.57-2.52 (1H, dd), 1.04-1.03 (3H, d), 0.83 (9H, s),0.00 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 631/633, [M+Na]⁺ 653/655, [M−H]⁻629/631.

Preparation 18:2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-chlorobenzyl)-acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.31 (1H, s), 7.28-7.25 (1H, d), 7.21-7.16(1H, m), 7.13-7.11 (1H, m), 7.03 (1H, s), 6.99-6.97 (2H, d), 6.69-6.67(1H, d), 4.70-4.67 (1H, t), 4.62-4.62 (2H, d), 4.32 (2H, s), 3.48 (2H,s), 2.88-2.83 (2H, m), 2.68-2.60 (2H, m), 2.55-2.50 (1H, dd), 1.03-1.02(2H, d), 0.83 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 597/599, [M+Na]⁺ 619/621, [M−H]⁻595/597.

Preparation 19:4-{([2-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoicacid

Prepared according to the procedure used for preparation 36, usingmethyl4-{([2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoate(Preparation 20), to give the title compound as a white solid which wasused without further purification.

¹H NMR (400 MHz, CD₃OD): δ=7.89-7.87 (2H, d), 7.34-7.20 (5H, m),7.15-7.09 (3H, m), 6.80-6.78 (1H, d), 5.00-4.97 (1H, m), 4.67-4.66 (2H,d), 4.40 (2H, s), 3.55 (2H, s), 3.45-3.38 (1H, m), 3.28-3.23 (1H, dd),3.15-3.11 (1H, dd), 3.03-2.98 (1H, dd), 2.72-2.66 (1H, dd), 1.17-1.16(3H, d), 0.86 (9H, s), 0.07 (3H, s), −0.12 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 607, [M+Na]⁺ 629, [M−H]⁻ 605.

CHN analysis: Found: C, 62.04%; H, 7.50%; N, 3.79%.C₃₄H₄₆N₂O₆Si+0.5MeOH+2.6H₂O requires C, 61.97%; H, 7.87%; N, 4.19%.

Preparation 20: Methyl-4-{([2-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoate

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as an orange oil.

¹H NMR (400 MHz, CD₃OD): δ=7.93-7.91 (2H, d), 7.33-7.31 (2H, d),7.21-7.13 (3H, m), 7.05 (1H, s), 7.00-6.97 (2H, m), 6.69-6.67 (1H, d),4.70-4.67 (1H, m), 4.62-4.61 (2H, d), 4.42 (2H, s), 3.87 (3H, s), 3.52(2H, s), 2.91-2.84 (2H, m), 2.69-2.60 (2H, m), 2.56-2.51 (1H, dd),1.04-1.02 (3H, d), 0.84 (9H, s), 0.01 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 621.

Preparation 21:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1R)-1-phenylethyl]acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD): δ=7.27-7.26 (4H, d), 7.21-7.09 (4H, m),7.01-6.95 (3H, m), 6.69-6.67 (1H, d), 5.00-4.95 (1H, q), 4.70-4.67 (1H,dd), 4.62-4.61 (2H, d), 3.46 (2H, s), 2.88-2.83 (2H, m), 2.69-2.61 (2H,m), 2.53-2.48 (1H, dd), 1.44-1.42 (3H, d), 1.02-1.01 (3H, d), 0.83 (9H,s), 0.00 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 577, [M+Na]⁺ 599, [M−H]⁻ 575.

Preparation 22:4-{(1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[2-(3,4-dihydroisoquinolin-2-(1H)-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.23-7.07 (7H, m), 7.03-6.92 (3H, m),6.68-6.66 (1H, d), 4.70-4.66 (3H, m), 4.61 (2H, s), 3.82 (2H, s),3.81-3.70 (2H, m), 2.90-2.81 (3H, m), 2.71-2.43 (4H, m), 1.02-0.94 (3H,m), 0.82 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 589, [M+Na]⁺ 611, [M−H]⁻ 587.

Preparation 23:4-{(1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[2-(7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2-(1H)-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.23-6.91 (6H, m), 6.71-6.55 (3H, m),4.69-4.64 (1H, m), 4.61 (2H, s), 4.61-4.56 (2H, m), 4.03-3.93 (2H, m),3.81 (2H, s), 3.76 (3H, s), 3.79-3.66 (2H, m), 2.90-2.40 (7H, m),1.38-1.33 (3H, m), 1.02-0.94 (3H, m), 0.82 (9H, s), −0.01 (3H, s), −0.21(3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 663, [M−H]⁻ 661.

Preparation 24:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-(4-chlorophenyl)ethyl]acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.15 (4H, m), 7.09-7.03 (3H, m),7.00-6.97 (3H, m), 6.69-6.66 (1H, d), 4.71-4.68 (1H, t), 4.60 (2H, d),3.38 (2H, s), 3.40-3.36 (2H, t), 2.93-2.85 (2H, m), 2.75-2.72 (2H, t),2.69-2.62 (2H, m), 2.57-2.52 (1H, dd), 1.06-1.04 (3H, d), 0.82 (9H, s),−0.01 (3H, s), −0.20 (3H, s), ppm.

LRMS (electrospray): m/z [M+H]⁺ 611, [M−H]⁻ 609.

Preparation 25:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-(4-ethylphenyl)ethyl]acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.18 (1H, s), 7.16-7.14 (1H, d), 7.06-6.95(8H, m), 6.67-6.65 (1H, d), 4.69-4.66 (1H, t), 4.60-4.59 (2H, d), 3.39(2H, s), 3.37-3.34 (2H, t), 2.92-2.84 (2H, m), 2.72-2.68 (2H, t),2.66-2.51 (5H, m), 1.19-1.16 (3H, t), 1.05-1.03 (3H, d), 0.81 (9H, s),−0.02 (3H, s), −0.21 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 605, [M−H]⁻ 603.

Preparation 26:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1,1-dimethyl-2-phenylethyl)acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.22-7.18 (2H, m), 7.14-7.11 (4H, m),7.03-6.95 (5H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, q), 4.61 (2H, d),3.37 (2H, s), 2.99 (2H, s), 2.92-2.84 (2H, m), 2.72-2.62 (2H, m),2.57-2.52 (1H, dd), 1.26 (6H, s), 1.04-1.03 (3H, d), 0.83 (9H, s), 0.00(3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 605, [M−H]⁻ 603.

Preparation 27:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-[2-(3,4-dimethoxyphenyl)ethyl]acetamide

Prepared according to the procedure used for preparation 1 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.19-7.14 (2H, m), 7.05-7.04 (1H, d),7.01-6.98 (3H, m), 6.82-6.77 (2H, m), 6.69-6.66 (2H, m), 4.71-4.69 (1H,m), 4.62-4.61 (2H, d), 3.78 (3H, s), 3.76 (3H, s), 3.41 (2H, s),3.41-3.37 (2H, t), 2.95-2.86 (2H, m), 2.73-2.69 (2H, t), 2.67-2.62 (2H,m), 2.57-2.52 (1H, dd), 1.06-1.04 (3H, d), 0.83 (9H, s), 0.00 (3H, s),−0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 637, [M−H]⁻ 635.

Preparation 28:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3,4-difluorobenzyl)acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.20-7.07 (5H, m), 7.04-6.97 (4H, m),6.97-6.69 (1H, d), 4.70-4.67 (1H, dd), 4.62-4.61 (2H, d), 4.31 (2H, s),3.49 (2H, s), 2.90-2.83 (2H, m), 2.69-2.60 (2H, m), 2.55-2.50 (1H, m),1.03-1.02 (3H, d), 0.83 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 599, [M−H]⁻ 597.

Preparation 29:4-{(1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-[{tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a yellow oil.

¹H NMR (400 MHz, CD₃OD): δ=7.26-7.13 (7H, m), 7.07 (1H, s), 6.99-6.97(1H, d), 6.94-6.91 (1H, dd), 6.66-6.64 (1H, d), 4.74 (2H, s), 4.67-4.64(1H, t), 4.61 (2H, d), 3.76 (2H, s), 3.34 (2H, s), 2.93-2.82 (2H, m),2.67-2.55 (3H, m), 1.06-1.04 (3H, d), 0.80 (9H, s), −0.03 (3H, s), −0.21(3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 575, [M+Na]⁺ 597, [M−H]⁻ 573.

Preparation 30:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylacetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2[(2R)-{[tert-butyl(dimethyl)silyl]ixy}-2-(4-hydroxy-3hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.53-7.51 (2H, d), 7.28-7.24 (2H, m), 7.18(3H, s), 7.11-7.03 (2H, m), 6.98-6.94 (1H, m), 6.68-6.66 (1H, d),4.69-4.66 (1H, m), 4.62-4.61 (2H, d), 3.62 (2H, s), 2.94-2.85 (2H, m),2.70-2.55 (3H, m), 1.07-1.05 (3H, d), 0.81 (9H, s), −0.02 (3H, s), −0.21(3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 549, [M+Na]⁺ 571, [M−H]⁻ 547.

Preparation 31:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1-naphthylmethyl)acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.96-7.94 (1H, d), 7.85-7.82 (1H, d),7.78-7.75 (1H, d), 7.55-7.35 (4H, m), 7.19-7.09 (3H, m), 6.98-6.93 (3H,m), 6.70-6.68 (1H, d), 4.79 (2H, s), 4.68-4.58 (3H, m), 3.47 (2H, s),2.82-2.72 (2H, m), 2.60-2.54 (2H, m), 2.45-2.40 (1H, m), 0.96-0.95 (3H,d), 0.83 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 613, [M+Na]⁺ 635, [M−H]⁻ 611.

Preparation 32:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-pyridin-2-ylethyl)acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=8.41-8.39 (1H, d), 7.68-7.64 (1H, m),7.23-7.14 (4H, m), 7.06-7.04 (1H, d), 6.98-6.96 (3H, d), 6.69-6.67 (1H,d), 3.53-3.50 (1H, t), 3.39 (2H, s), 2.94-2.84 (4H, m), 2.67-2.61 (2H,m), 2.55-2.50 (1H, m), 1.04-1.03 (3H, d), 0.82 (9H, s), −0.01 (3H, s),−0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 578, [M+Na]⁺ 600, [M−H]⁻ 576.

Preparation 33:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(2R)-2-phenylpropyl]acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.24-7.11 (7H, m), 7.00-6.94 (4H, m),6.68-6.66 (1H, d), 4.69-4.66 (1H, m), 4.61-4.60 (2H, d), 3.31-3.28 (3H,m), 2.93-2.83 (3H, m), 2.78 (1H, s), 2.66-2.60 (2H, m), 2.53-2.48 (1H,m), 1.19-1.17 (3H, d), 1.03-1.01 (3H, d), 0.82 (9H, s), −0.02 (3H, s),−0.21 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 591, [M+Na]⁺ 613, [M−H]⁻ 589.

Preparation 34:N-Benzyl-2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.52-7.36 (6H, m), 7.30-7.25 (2H, m),7.19-7.16 (3H, m), 6.89-6.87 (1H, d), 4.90-4.87 (1H, m), 4.83-4.73 (4H,m), 3.97-3.95 (2H, d), 3.11-3.03 (5H, m), 2.88-2.79 (2H, m), 2.75-2.70(1H, m), 1.23-1.20 (3H, m), 0.79 (9H, s), −-0.05 (3H, s), −0.23 (3H, s)ppm.

LRMS (electrospray): m/z [M+H]⁺ 577, [M+Na]⁺ 599, [M−H]⁻ 575.

Preparation 35:2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[3-(4-fluorophenyl)propyl]acetamide

Prepared according to the procedure used for preparation 5 using(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid (Preparation 36) and the appropriate amine to give the titlecompound as a white foam.

¹HNMR (400 MHz, CD₃OD) δ: 7.22-6.92 (10H, m), 6.69 (1H, d), 4.71-4.66(1H, m), 4.62 (2H, s), 3.44 (2H, s), 3.20-3.16 (2H, m), 2.94-2.52 (7H),m), 1.80-1.73 (2H, m), 1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.19(3H, s) ppm.

LRMS (electrospray): 609 [M+H]⁺, 631 [M+Na]⁺

Preparation 36:(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-aceticacid

A solution of methyl(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate(Preparation 37) (7.04 g, 14.4 mmol) in tetrahydrofuran (40 ml) wastreated with lithium hydroxide (28.9 ml of a 1M aqueous solution, 28.9mmol) and the reaction left to stir at room temperature for 16 hours.Hydrochloric acid (28.9 ml of a 1M aqueous solution, 28.9 mmol) wasadded and then the tetrahydrofuran was removed in vacuo. The remainingaqueous layer was decanted and the residue washed with further water (10ml). The residue was redisolved in methanol (30 ml) and the solventremoved in vacuo to give the title compound as a colorless foam (5.95 g)which was used without further purification.

¹H NMR (400 MHz, CD₃OD): δ=7.32 (1H, s), 7.25-7.18 (2H, m), 7.13 (1H,s), 7.12-7.10 (1H, d), 7.02-7.01 (1H, d), 6.79-6.77 (1H, d), 4.98-4.95(1H, m), 4.65-4.64 (2H, d), 3.48 (2H, s), 3.48-3.43 (1H, m), 3.28-3.23(1H, dd), 3.13-3.09 (1H, dd), 2.98-2.93 (1H, dd), 2.77-2.72 (1H, dd),1.23-1.21 (3H, d), 0.86 (9H, s), 0.06 (3H, s), −0.13 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 474, [M+Na]⁺ 496, [M−H]⁻ 472.

CHN analysis: Found C, 64.15%; H, 8.25%; N, 2.84%; C₂₆H₃₉NO₅Si+0.7H₂Orequires C, 64.22%; H, 8.37%; N, 2.88%.

Preparation 37:Methyl-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate

A suspension of methyl(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate(Preparation 38) (5.27 g, 9.12 mmol) and 10% palladium on carbon (1.00g) in ethanol (50 ml) was stirred under an atmosphere of hydrogen (60psi) at room temperature for 16 hours. The catalyst was filtered offthrough arbocel and the filtrate concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel eluting withdichloromethane:methanol:880 ammonia (96:4:0.4 changing to 95:5:0.5, byvolume) to give the title compound as a pale yellow oil (1.99 g) whichwas used without further purification.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.17 (2H, m), 7.11-7.09 (1H, d),7.03-6.98 (3H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t), 4.62-4.61 (2H,d), 3.67 (3H, s), 3.59 (2H, s), 2.96-2.86 (2H, m), 2.69-2.55 (3H, m),1.07-1.05 (3H, d), 0.82 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 488, [M+Na]⁺ 510, [M−H]⁻ 486

Preparation 38:Methyl-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate

A solution of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 39) (12.5 g, 27.7 mmol) andthe amine from preparation 27 (11.5 g, 55.4 mmol) in dichloromethane(130 ml) was heated to 90° C., allowing the dichloromethane toevaporate. The resulting melt was left at 90° C. for a further 16 hours.The reaction mixture was cooled to room temperature and purified byflash column chromatography on silica gel eluting withdichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97:3:0.3, byvolume) to give the title compound (12.1 g) as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.47-7.45 (2H, m), 7.39-7.29 (4H, m),7.19-7.15 (1H, t), 7.13-7.07 (2H, m), 7.03 (1H, s), 7.01-6.99 (1H, d),6.93-6.91 (1H, d), 5.12 (2H, s), 4.76-4.73 (1H, t), 4.67-4.66 (2H, d),3.66 (3H, s), 3.58 (2H, s), 2.95-2.80 (2H, m), 2.68-2.55 (3H, m),1.06-1.05 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 578, [M+Na]⁺ 600.

Preparation 39: [2-(Benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol

Borane dimethylsulfide complex (42.4 ml of 10M solution intetrahydrofuran, 424 mmol) was added dropwise to a solutionmethyl-2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzoate(Preparation 40) (91.0 g, 189 mmol) in tetrahydrofuran (1600 ml). Theresulting mixture was then heated to reflux for 2 hours and then cooledto 0° C. before quenching with methanol (270 ml). The mixture was leftto stir at room temperature for 16 hours and then the solvent removed invacuo. The residue was partitioned between dichloromethane (500 ml) andwater (500 ml). The aqueous phase was separated and extracted withdichloromethane (500 ml) and the combined organic extracts washed withbrine (500 ml), dried (magnesium sulfate) and the solvent removed invacuo. The residue was purified by flash column chromatography on silicagel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, byvolume) to give the title compound (68.7 g) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ=7.42-7.36 (5H, m), 7.29-7.25 (3H, m), 6.94(1H, d), 5.12 (2H, s), 4.84-4.81 (1H, m), 4.74 (2H, s), 3.48-3.40 (2H,m), 0.90 (9H, s), 0.11 (3H, s), −0.07 (3H, s) ppm.

LRMS (electrospray): m/z [M+Na]⁺ 473/475.

Preparation 40:Methyl-2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzoate

A solution of methyl2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate (71.0 g, 195mmol), imidazole (18.5 g, 272 mmol), tert-butyldimethylsilyl chloride(32.2 g, 214 mmol) and 4-(N,N-dimethylamino)pyridine (440 mg, 3.60 mmol)in N,N-dimethylformamide (270 ml) was left to stir at room temperatureunder a nitrogen atmosphere for a period of 24 hours. The solvent wasremoved in vacuo and the residue partitioned between ethyl acetate (500ml) and water (500 ml). The organic phase was separated and washed with2N aqueous hydrochloric acid (2×500 ml), saturated aqueous sodiumbicarbonate (2×500 ml), brine (500 ml), dried (magnesium sulfate) andthe solvent removed in vacuo to give the title compound as a colourlessoil (91.0 g).

¹H NMR (400 MHz, CDCl₃): δ=7.81 (1H, bs), 7.51-7.30 (6H, m), 7.01 (1H,d), 5.19 (2H, s), 4.85-4.82 (1H, m), 3.91 (3H, s), 3.48-3.39 (2H, m),0.90 (9H, s), 0.11 (3H, s), −0.08 (3H, s) ppm.

LRMS (electrospray): m/z [M+Na]⁺ 501/503.

Preparation 41: Methyl-{3-[(2R)-2-aminopropyl]phenyl}acetate

A solution ofmethyl-[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetatehydrochloride (Preparation 42) (7.69 g, 22.0 mmol) and ammonium formate(6.94 g, 110 mmol) was heated to 75° C. in the presence of 20% palladiumhydroxide-on-charcoal (Pd(OH)₂/C, 2.00 g). After 90 minutes the reactionmixture was cooled to room temperature, filtered through arbocel and thefiltrate concentrated in vacuo. The residue was partitioned betweendichloromethane (100 ml) and 880 ammonia (100 ml) and the organic phaseseparated. The aqueous phase was extracted dichloromethane (100 ml) andthe combined organic extracts dried (magnesium sulfate) and reduced invacuo to give the title compound as a colourless oil (4.78 g).

¹H NMR (400 MHz, CD₃OD): δ=7.27-7.23 (1H, t), 7.13-7.09 (3H, m), 3.67(3H, s), 3.63 (2H, s), 3.12-3.05 (1H, m), 2.67-2.57 (2H, m), 1.06 (3H,d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 208, [M+Na]⁺ 230.

Preparation 42:Methyl-[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetatehydrochloride

A solution of methyl-[3-(2-oxopropyl)phenyl]acetate (Preparation 43)(8.50 g, 41.2 mmol), (R)-α-methyl benzylamine (4.8 ml, 37.2 mmol),sodium triacetoxyborohydride (11.6 g, 56.0 mmol) and acetic acid (2.2ml, 38.0 mmol) in dichloromethane (400 ml) was stirred at roomtemperature for 48 hours. The reaction mixture was quenched by additionof saturated aqueous sodium bicarbonate (200 ml) and allowed to stiruntil effervescence ceased. The organic phase was separated and theaqueous phase extracted with dichloromethane (100 ml). The combinedorganic extracts were dried (magnesium sulfate) and reduced in vacuo.Purification by flash column chromatography eluting withdichloromethane:methanol: 880 ammonia (99:1:0.1 to 95:5:0.5 by volume)gave a 4:1 mixture of diastereomers (R,R major) as a pale yellow oil(8.71 g). Treatment with hydrogen chloride (40 ml of a 1M solution inmethanol, 40.0 mmol) followed by three successive crystallisations(diisopropylether/methanol) gave the title compound as a whitecrystalline solid (5.68 g).

¹H NMR (400 MHz, CD₃OD): δ=7.52-7.48 (5H, m), 7.28-7.25 (1H, m),7.18-7.16 (1H, m), 7.02-6.99 (2H, m), 4.59 (1H, q), 3.62 (2H, s), 3.30(3H, s), 3.30-3.25 (1H, m), 3.26-3.15 (1H, m), 2.66-2.60 (1H, m), 1.68(3H, d), 1.18, (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 312, [M+Na]⁺ 334.

Preparation 43: Methyl-[3-(2-oxopropyl)phenyl]acetate

Tributyltin methoxide (28.3 ml, 98.0 mmol),methyl-(3-bromophenyl)acetate (Preparation 44) (15.0 g, 65.0 mmol),isopropenyl acetate (10.8 ml, 98.0 mmol), palladium(II)acetate (750 mg,3.30 mmol) and tri-ortho-tolylphosphine (2.00 g, 6.5 mmol) were stirredtogether in toluene (75 ml) at 100° C. under nitrogen for 5 hours. Aftercooling the reaction was diluted with ethyl acetate (150 ml) and 4Maqueous potassium fluoride solution (90 ml) and stirred for 15 minutes.The mixture was filtered through arbocel and the organic phase separatedand reduced in vacuo. The residue was purified by flash columnchromatography silica gel eluting with a solvent gradient of diethylether:pentane (0:100 to 25:75, by volume) changing to dichloromethane togive the title compound as a pale yellow oil (12.6 g).

¹H NMR (400 MHz, CDCl₃): δ=7.30 (1H, t), 7.19 (1H, d), 7.13-7.10 (2H,m), 3.69 (5H, s), 3.61 (2H, s), 2.15 (3H, s) ppm.

LRMS (electrospray): m/z [M+NH₄]⁺ 224, [M+Na]⁺ 229.

Preparation 44: Methyl-(3-bromophenyl)acetate

Acetyl chloride (0.70 ml, 9.30 mmol) was slowly added to a solution of(3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at0° C. under nitrogen and the reaction was allowed to warm gradually toroom temperature over a period of 5 hours. The solvent was removed invacuo and the residual oil was dissolved in dichloromethane, dried(sodium sulfate) and concentrated in vacuo to give the title compound asa colourless oil (20.6 g).

¹H NMR (400 MHz, CDCl₃): δ=7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70(3H, s), 3.59 (2H, s) ppm.

LRMS (electrospray): m/z [M+Na]⁺ 253.

Preparation 45:3-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2,6-dichlorobenzyl)propanamide

Prepared using the method for preparation 5 using3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid (Preparation 51) and the appropriate amine to give the titlecompound as a white solid.

¹H NMR (400 MHZ, CD₃OD): δ=7.39-7.37 (2H, d), 7.28-7.24 (1H, m),7.20-7.19 (1H, d), 7.14-7.10 (1H, t), 7.03-6.97 (2H, m), 6.94-6.90 (2H,m), 6.69-6.67 (1H, d), 4.73-4.69 (1H, t), 4.64-4.56 (4H, m), 2.95-2.84(4H, m), 2.69-2.63 (2H, m), 2.56-2.50 (1H, m), 2.48-2.44 (2H, t),1.06-1.04 (3H, d), 0.82 (9H, s), −0.01 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 645/647, [M+Na]⁺ 667/669, [M−H]⁻643/645.

Preparation 46:3-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2,6-dimethoxybenzyl)propanamide

Prepared according to the procedure used for preparation 1 using3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid (Preparation 51) and the appropriate amine, substitutingdichloromethane instead of ethyl acetate as the extraction solvent togive the title compound as a yellow foam.

¹H NMR (400 MHz, CD₃OD): δ=7.20-7.15 (2H, m), 7.09-7.06 (1H, t),6.98-6.93 (2H, m), 6.89-6.86 (2H, m), 6.66-6.64 (1H, d), 6.57-6.55 (2H,d), 4.70-4.67 (1H, t), 4.57-4.56 (2H, d), 4.34 (2H, s), 3.74 (6H, s),2.94-2.86 (2H, m), 2.81-2.77 (2H, t), 2.67-2.59 (2H, m), 2.52-2.46 (1H,dd), 2.39-2.35 (2H, t), 1.02-1.00 (3H, d), 0.78 (9H, s), −0.04 (3H, s),−0.23 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 637, [M+Na]⁺ 659, [M−H]⁻ 635.

Preparation 47:3-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-ethoxybenzyl)propanamide

Prepared according to the procedure used for preparation 1 using3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid (Preparation 51) and the appropriate amine, substitutingdichloromethane instead of ethyl acetate as the extraction solvent, anddichloromethane:methanol: 880 ammonia (98:2:0.2 by volume) instead of(95:5:0.5 by volume) as column eluent to give the title compound as acolourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.17-7.07 (3H, m), 7.00-6.98 (1H, d),6.94-6.88 (4H, m), 6.84-6.82 (1H, d), 6.76-6.72 (1H, t), 6.64-6.62 (1H,d), 4.67-4.64 (1H, t), 4.57-4.56 (2H, d), 4.28 (2H, s), 4.01-3.96 (2H,q), 2.90-2.82 (4H, m), 2.63-2.57 (2H, m), 2.51-2.45 (3H, m), 1.37-1.33(3H, t), 1.01-0.99 (3H, d), 0.79 (9H, s), −0.04 (3H, s), −0.23 (3H, s)ppm.

LRMS (electrospray): m/z [M+H]⁺ 621, [M−H]⁻ 620.

Preparation 48:3-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3,4-dimethylbenzyl)propanamide

Prepared according to the procedure used for preparation 1 using3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid (Preparation 51) and the appropriate amine, substitutingdichloromethane instead of ethyl acetate as the extraction solvent, anddichloromethane:methanol: 880 ammonia (98:2:0.2 by volume) instead of(95:5:0.5 by volume) as column eluent to give the title compound as awhite foam.

¹H NMR (400 MHz, CD₃OD): δ=7.19-7.18 (1H, d), 7.15-7.11 (1H, t),7.04-6.92 (6H, m), 6.84-6.82 (1H, d), 6.68-6.66 (1H, d), 4.70-4.67 (1H,t), 4.61-4.60 (2H, d), 4.23 (2H, s), 2.90-2.84 (4H, m), 2.64-2.59 (2H,m), 2.53-2.46 (3H, m), 2.20 (6H, s), 1.03-1.02 (3H, d), 0.82 (9H, s),−0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 605, [M+Na]⁺ 627, [M−H]⁻ 603.

Preparation 49:3-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2,3-dihydro-1H-inden-2-yl)propanamide

Prepared according to the procedure used for preparation13-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid (Preparation 51) and the appropriate amine, substitutingdichloromethane instead of ethyl acetate as the extraction, anddichloromethane:methanol: 880 ammonia (97:3:0.3 by volume) instead of(95:5:0.5 by volume) as column eluent to give the title compound as awhite foam.

¹H NMR (400 MHz, CD₃OD): δ=7.19-7.09 (6H, m), 7.02-6.90 (4H, m),6.68-6.66 (1H, d), 4.70-4.67 (1H, dd), 4.60 (2H, s), 4.56-4.49 (1H, m),3.21-3.15 (2H, dd), 2.91-2.81 (4H, m), 2.73-2.68 (2H, dd), 2.65-2.60(2H, dd), 2.54-2.49 (1H, dd), 2.43-2.40 (2H, t), 1.04-1.02 (3H, d), 0.82(9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 603, [M+Na]⁺ 625, [M−H]⁻ 601.

Preparation 50:4-{(1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}-2-[((1R)-2-{3-[3-(3,4-dihydroisoquinolin-2-(1H)-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]ethyl}-2-(hydroxymethyl)phenol

Prepared according to the procedure used for preparation 1 using3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid (Preparation 51) and the appropriate amine, substitutingdichloromethane instead of ethyl acetate as the extraction solvent, anddichloromethane:methanol: 880 ammonia (96:4:0.4 by volume) instead of(95:5:0.5 by volume) as column eluent to give the title compound as awhite foam.

¹H NMR (400 MHz, CD₃OD): δ=7.19 (1H, s), 7.16-7.01 (5H, m), 6.99-6.90(3H, m), 6.84-6.82 (1H, d), 6.70-6.67 (1H, m), 4.71-4.68 (1H, dd),4.65+4.54 (2H, m), 4.62-4.60 (2H, m), 3.76-3.60 (2H, m), 2.93-2.85 (4H,m), 2.80-2.69 (4H, m), 2.66-2.53 (2H, m), 2.50-2.45 (1H, dd), 1.03-1.00(3H, m), 0.82 (9H, s), −0.01 (3H, s), −0.19 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 603, [M+Na]⁺ 625, [M−H]⁻ 601.

Preparation 51:3-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoicacid

Prepared according to the procedure used for preparation 36, usingmethyl-3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoate(Preparation 52) to give the title compound as a brown solid.

¹H NMR (400 MHz, CD₃OD): δ=7.27 (1H, s), 7.19-7.14 (1H, t), 7.09-7.02(3H, m), 6.95-6.93 (1H, d), 6.75-6.73 (1H, d), 4.92-4.90 (1H, m),4.61-4.60 (2H, d), 3.37-3.32 (1H, m), 3.20-3.15 (1H, m), 3.04-3.00 (1H,dd), 2.91-2.83 (3H, m), 2.68-2.62 (1H, m), 2.45-2.40 (2H, t), 1.15-1.14(3H, d), 0.81 (9H, s), −0.01 (3H, s), −0.18 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 488, [M+Na]⁺ 510, [M−H]⁻ 486.

Preparation 52:Methyl-3-(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoate

Prepared according to the procedure used for preparation 37, usingmethyl-3-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoate(Preparation 53) to give the title compound as a brown oil.

¹H NMR (400 MHz, CD₃OD): δ=7.08-7.15 (2H, m), 6.99-6.88 (4H, m),6.65-6.62 (1H, d), 4.67-4.64 (1H, m), 4.58-4.57 (2H, d), 3.59 (3H, s),2.90-2.80 (4H, m), 2.61-2.49 (5H, m), 1.01-1.00 (3H, d), 0.78 (9H, s),−0.06 (3H, s), −0.24 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 502, [M+Na]⁺ 524, [M−H]⁻ 500.

Preparation 53:Methyl-3-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoate

Prepared according to the procedure used for preparation 38 usingmethyl-3-[(2R)-2-aminopropyl)phenyl]propanoate (Preparation 54) and[2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol(Preparation 39) to give the title compound as a brown oil.

¹H NMR (400 MHz, CD₃OD): δ=7.43-7.24 (6H, m), 7.11-7.04 (2H, m),6.69-6.95 (1H, d), 6.91-6.86 (3H, m), 5.07 (2H, s), 4.71-4.66 (1H, m),4.63-4.62 (2H, d), 3.58 (3H, s), 2.89-2.79 (4H, m), 2.63-2.47 (5H, m),1.02-1.00 (3H, d), 0.78 (9H, s), −0.05 (3H, s), −0.23 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 592, [M+Na]⁺ 614.

Preparation 54: Methyl-3-[(2R)-2-aminopropyl)phenyl]propanoate

Prepared according to the procedure used for preparation 41, usingmethyl-[3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-propanoatehydrochloride (Preparation 55) to give the title compound as a brownoil.

¹H NMR (400 MHz, CD₃OD): δ=7.21-7.17 (1H, t), 7.03-7.01 (3H, m), 3.61(3H, s), 3.11-3.03 (1H, m), 2.91-2.87 (2H, t), 2.64-2.54 (4H, m),1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 222.

Preparation 55:Methyl-[3-((2R)-2{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-propanoatehydrochloride

Prepared according to the procedure used for preparation 52, usingmethyl-3-[3-(2-oxopropyl)phenyl]propanoate (Preparation 56) to give thetitle compound as a white crystalline solid.

¹H NMR (400 MHz, CD₃OD): δ=7.54-7.47 (5H, m), 7.23-7.19 (1H, t),7.12-7.10 (1H, d), 6.92-6.91 (2H, d), 4.64-4.59 (1H, q), 3.61 (3H, s),3.34-3.29 (1H, m), 3.20-3.12 (1H, m), 2.89-2.85 (2H, t), 2.62-2.56 (3H,m), 1.71-1.69 (3H, d), 1.18-1.16 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 326.

Preparation 56: Methyl-3-[3-(2-oxopropyl)phenyl]propanoate

Prepared according to the procedure used for preparation 37 using methyl(2E)-3-[3-(2-oxopropyl)phenyl]acrylate (Preparation 57) to give thetitle compound as an orange oil.

¹H NMR (400 MHz, CD₃OD): δ=7.27-7.23 (1H, q), 7.11-7.09 (1H, d),7.05-7.04 (2H, d), 3.66 (5H, s), 2.96-2.92 (2H, t), 2.64-2.60 (2H, t),2.14 (3H, s) ppm.

LRMS (electrospray): m/z [M+Na]⁺ 243, [M−H]⁻ 219.

Preparation 57: Methyl (2E)-3-[3-(2-oxopropyl)phenyl]acrylate

A solution of 3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate(40.4 g, 469 mmol), palladium(II)acetate (7.9 g, 35.2 mmol),tri-ortho-tolylphosphine (21.4 g, 70.4 mmol) and triethylamine (82 ml)in acetonitrile (900 ml) was heated at reflux under a nitrogenatmosphere for a period of 16 hours. The reaction mixture was cooled toroom temperature and the solvent removed in vacuo. Purification by flashcolumn chromatography eluting with pentane:ethyl acetate (90:10 changingto 70:30 by volume) gave the title compound as an orange oil (54.3 g).

¹H NMR (400 MHz, CD₃OD): δ=7.66-7.62 (1H, d), 7.41-7.39 (1H, d),7.34-7.31 (2H, t), 7.20-7.18 (1H, d), 6.43-6.39 (1H, d), 3.77 (3H, s),3.70 (2H, s), 2.15 (3H, s) ppm.

LRMS (electrospray): m/z [M+Na]⁺ 241, [M−H]⁻ 217.

Preparation 58:Methyl-3-{3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]phenyl}propanoate

Ammonium fluoride (2.80 g, 75.5 mmol) was added in one portion to asolution ofmethyl-3-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoate(Preparation 53) (4.47 g, 7.55 mmol) in water (20 ml) and methanol (30ml) at room temperature. The reaction was heated at 40° C. for 18 hoursand then allowed to cool to room temperature. The methanol was removedin vacuo and the resulting aqueous extracted with dichloromethane (3×75ml), the combined organics were washed with water (25 ml), dried (sodiumsulfate) and the solvent removed in vacuo to yield an orange foam. Thiswas purified by flash column chromatography on silica gel eluting withdichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give thetitle compound as a yellow oil (3.21 g).

¹H NMR (400 MHz, CD₃OD): δ=7.46-7.44 (2H, d), 7.38-7.28 (4H, m),7.15-7.11 (2H, m), 7.00-6.90 (4H, m), 5.12 (s, 2H), 4.67-4.63 (3H, m),3.62 (3H, s), 2.96-2.84 (4H, m), 2.74-2.66 (2H, m), 2.61-2.55 (3H, m),1.09-1.07 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 478, [M+Na]⁺ 500.

Preparation 59:Methyl3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoate

Prepared according to the procedure used for preparation 37 usingmethyl-3-{3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]phenyl}propanoate(Preparation 58), substituting dichloromethane:methanol: 880 ammonia(95:5:0.5 changing to 90:10:1 by volume) as column eluent to give thetitle compound as a colourless oil.

¹H NMR (400 MHz, CD₃OD): δ=7.21 (1H, m), 7.16-7.13 (1H, t), 7.02-7.00(2H, m), 6.97-6.93 (2H, m), 6.70-6.68 (1H, d), 3.63-3.60 (3H, m), 3.34(3H, s), 2.95-2.84 (4H, m), 2.72-2.65 (2H, m), 2.61-2.53 (3H, m),1.07-1.05 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 388, [M+Na]⁺ 410, [M−H]⁻ 386.

Preparation 60:3-{3-[(2R)-2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoicacid

Prepared according to the procedure used for preparation 36 usingmethyl-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoateto give the title compound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.17-7.13 (3H, m), 7.35-7.33 (1H, m),7.24-7.20 (1H, m), 7.07-7.03 (2H, d), 6.79-6.77 (1H, d), 4.87 (1H, s),4.65 (2H, s), 3.52-3.47 (1H, m), 3.16-3.06 (3H, m), 2.91-2.87 (2H, t),2.77-2.71 (1H, m), 2.48-2.44 (2H, t), 1.23-1.21 (3H, d) ppm.

LRMS (electrospray): m/z [M+H]⁺ 374, [M−H]⁻ 372.

Preparation 61:(4-{2-[2-(tert-Butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]propyl}phenyl)acetic acid

Prepared according to the procedure used for preparation 36, usingmethyl-(4-{2-(2R)-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]propyl}phenyl)acetate (Preparation 62) to give thetitle compound as a brown solid.

¹H NMR (400 MHz, CD₃OD): δ 7.15 (2H, d), 6.92 (2H, m), 7.00 (1H, d),6.83 (1H, m), 6.64 (2H, bd), 4.67 (1H, s), 4.60 (2H, m), 3.43 (2H, m),2.71-2.92 (3H, m), 2.55 (2H, m), 1.04 (3H, m), 0.83 (9H, s), 0.00 (3H,s), −0.18 (3H, s).

LRMS (electrospray): m/z [M−H]⁺ 472.

Preparation 62:Methyl-(4-{2-(2R)-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]propyl}phenyl)acetate

Prepared according to the procedure used for preparation 37, usingmethyl-(4-{(2R)-2-[(2R)-2-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(tert-butyldimethylsilanyloxy)ethylamino]propyl}phenyl)acetate(Preparation 63) to give the title compound as a yellow coloured foam.

¹H NMR (400 MHz, CDCl₃): δ 7.14 (2H, d), 7.04 (1H, d), 7.02 (1H, d),7.00 (1H, d), 6.90 (1H, d), 6.70 (1H, d), 4.76 (1H, s), 4.73 (2H, s),3.71 (3H, s), 3.59 (2H, s), 2.92 (2H, m), 2.73 (1H, m), 2.66 (2H, m),1.12 (3H, m), 0.81 (9H, s), −0.02 (3H, s), −0.19 (3H, s).

LRMS (electrospray): m/z [M+H]⁺ 488, [M+Na]⁺ 510.

Preparation 63:Methyl-(4-{(2R)-2-[(2R)-2-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(tert-butyldimethylsilanyloxy)ethylamino]propyl}phenyl)acetate

Methyl-{4-[(2R)-2-amino-propyl]phenyl}acetate (Preparation 64) (7.00 g,33.8 mmol),[2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol(Preparation 39) (15.2 g, 33.8 mmol) and diisopropylethylamine (4.36 g,33.8 mmol) were heated in dimethylsulfoxide (50 ml) at 90° C. undernitrogen for 16 hours. The mixture was cooled and diluted with ethylacetate (250 ml) and basified with 1M aqueous sodium hydroxide. Theaqueous was extracted with ethyl acetate (250 ml) and the combinedorganics washed with brine (3×200 ml) and dried (magnesium sulfate). Thecrude material was purified by chromatography (90:10dichloromethane:methanol) to furnish an orange coloured oil (9.86 g).

¹H NMR (400 MHz, CDCl₃): δ 7.32-7.43 (5H, m), 7.13 (1H, d), 7.17 (1H,m), 7.15 (2H, d), 7.07 (2H, d), 6.88 (1H, d), 5.10 (2H, s), 4.73 (1H,m), 4.70 (2H, d), 3.67 (3H, s), 3.57 (2H, s), 2.68-2.91 (4H, m), 2.48(1H, m), 2.37 (1H, m), 1.01 (3H, d), 0.84 (9H, s), 0.00 (3H, s), −0.18(3H, s).

LRMS (electrospray): m/z [M+H]⁺ 578, [M+Na]⁺ 600.

Preparation 64: Methyl{4-[(2R)-2-amino-propyl]phenyl}acetate

Prepared according to the procedure used for preparation 41, usingmethyl-(4-{(2R)-2-[(1R)-1-phenylethylamino]propyl}phenyl)acetatehydrochloride (Preparation 65) to give the title compound as whitecrystals.

¹H NMR (400 MHz, CDCl₃): δ 7.22 (2H, d), 7.17 (2H, d), 3.69 (3H, s),3.60 (2H, s), 3.35 (1H, m), 2.79 (1H, m), 1.24 (3H, d).

LRMS (electrospray): m/z [M+H]⁺ 208, [M+Na]⁺ 230.

Preparation 65:Methyl-(4-{(2R)-2-[(11R)-1-phenylethylamino]propyl}phenyl)acetatehydrochloride

Prepared according to the procedure used for preparation 42, usingmethyl-[4-(2-oxo-propyl)phenyl]acetate (Preparation 66) to give thetitle compound as white crystals.

¹H NMR (400 MHz, CD₃OD): δ 7.53 (5H, m), 7.21 (2H, d), 7.06 (2H, d),4.61 (1H, q), 3.66 (3H, s), 3.62 (2H, s), 3.30 (2H, m), 3.18 (1H, m),2.63 (1H, dd), 1.70 (3H, d), 1.18 (3H, d).

LRMS (electrospray): m/z [M+H]⁺ 312, [M+Na]⁺ 334.

Preparation 66: Methyl-[4-(2-oxo-propyl)phenyl]acetate

Prepared according to the procedure used for preparation 43, usingmethyl-4-bromophenylacetate to give the title compound as a clear oil.

LRMS (electrospray): m/z [M+Na]⁺ 229, [M−H]⁻ 205.

Preparation 67:2-{4-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-fluoro-5-(trifluoromethyl)benzyl]acetamide

Prepared according to the procedure used for preparation 3 using(4-{2-[2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]propyl}phenyl)aceticacid (Preparation 61) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.55 (2H, m), 7.31-6.82 (7H, m), 6.62 (1H,d), 6.05 (1H, m), 4.75 (2H, s), 4.61 (2H, t), 4.55 (2H, d), 3.68 (2H,s), 2.95 (1H, m), 2.83 (1H, m), 2.56 (3H, m), 1.05 (3H, d), 0.90 (9H,s), 0.00 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 649.

Preparation 68:2-{4-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)acetamide

Prepared according to the procedure used for preparation 3 using(4-{2-[2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]propyl}phenyl)aceticacid (Preparation 61) and the appropriate amine to give the titlecompound as a white foam.

¹H NMR (400 MHz, CD₃OD): δ=7.31-6.85 (11H, m), 6.62 (1H, d), 5.63 (1H,m), 4.75 (2H, s), 4.66 (1H, t), 3.55 (2H, m), 3.48 (2H, s), 2.88 (7H,m), 1.05 (3H, d), 0.90 (9H, s), 0.00 (3H, s), −0.20 (3H, s) ppm.

LRMS (electrospray): m/z [M+H]⁺ 577, [M+Na]⁺ 599, [M−H]⁻ 575.

Abbreviations

TBDMS=tert-butyl(dimethyl)silyl

In Vitro Activity of the Compounds of Formula (1)

The ability of the compounds of the formula (1) to act as potent β2agonists therefore mediating smooth muscle relaxation may be determinedby the measure of the effect of beta-2 adrenergic receptor stimulationon electrical field stimulated-contraction of guinea pig trachea strips.

Guinea-Pig Trachea

Male, Dunkin-Hartley guinea pigs (475-525 g) are killed by CO₂asphyxiation and exsanguination from the femoral artery and the tracheais isolated. Four preparations are obtained from each animal, startingthe dissection immediately below the larynx and taking 2.5 cm length oftrachea. The piece of trachea is opened by cutting the cartilageopposite the trachealis muscle, then transverse sections, 3-4 cartilagerings wide, are cut. The resulting strip preparations are suspended in 5ml organ baths using cotton threads tied through the upper and lowercartilage bands. The strips are equilibrated, un-tensioned, for 20minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μMIndomethacin (Sigma I7378), 10 μM Guanethidine (Sigma G8520) and 10 μMAtenolol (Sigma A7655), heated at 37° C. and gassed with 95% O₂/5% CO₂,before applying an initial tension of 1 g. The preparations are allowedto equilibrate for a further 30-45 minutes, during which time they arere-tensioned (to 1 g) twice at 15-minute intervals. Changes in tensionare recorded and monitored via standard isometric transducers coupled toa data-collection system (custom-designed at Pfizer). Following thetensioning equilibration, the tissues are subjected to electrical fieldstimulation (EFS) using the following parameters: 10 strains every 2minutes, 0.1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts)continuously throughout the length of the experiment. EFS ofpost-ganglionic cholinergic nerves in the trachea results in monophasiccontractions of the smooth muscle and twitch height is recorded. Theorgan baths are constantly perfused with the above-described KrebsRinger buffer by means of a peristaltic pump system (pump flow rate 7.5ml/minute) throughout the experiment, with the exception of when abeta-2 agonist according to the present invention is added, the pump isthen stopped for the time of the cumulative dosing to the bath andstarted again after maximal response is reached for the wash-out period.

Experimental Protocol for Assessment of Potency and Efficacy

Following equilibration to EFS, the peristaltic pump is stopped and thepreparations ‘primed’ with a single dose of 300 nM isoprenaline (SigmaI5627) to establish a maximal response in terms of inhibition of thecontractile EFS response. The isoprenaline is then washed out over aperiod of 40 minutes. Following the priming and wash-out recovery, astandard curve to isoprenaline is carried out on all tissues(Isoprenaline Curve 1) by means of cumulative, bolus addition to thebath using half log increments in concentration. The concentration rangeused is 1^(e-9) to 1^(e)/3^(e-6) M. At the end of the isoprenaline curvethe preparations are washed again for 40 minutes before commencing asecond curve, either to isoprenaline (as internal control) or a beta-2agonist according to the present invention. Beta-2 agonist responses areexpressed as percentage inhibition of the EFS response. Data for beta-2agonist are normalised by expressing inhibition as a percentage of themaximal inhibition induced by isoprenaline in Curve 1. The EC₅₀ valuefor beta-2 agonist according to the present invention refers to theconcentration of compound required to produce half maximal effect. Datafor beta-2 agonists according to the present invention are thenexpressed as relative potency to isoprenaline defined by the ratio (EC₅₀beta-2 agonist)/(EC₅₀ Isoprenaline).

Confirmation of Beta-2 Mediated Functional Activity

Beta-2 agonist activity of test compounds is confirmed using theprotocol above, however, prior to constructing the curve to beta-2agonist according to the present invention, the preparations arepre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (aselective β₂ antagonist) which results in the case of a beta-2 mediatedeffect in a rightward-shift of the test compound dose response curve.

It has thus been found that the compounds of formula (1) according tothe present invention that have been tested show a relative potency toIsoprenaline which is comprised between 0.002 and 2.0.

According to another alternative, the agonist potency for the β₂receptor of the compounds of the formula (1) may also be determined bythe measure of the concentration of compound according to the presentinvention required to produce half maximal effect (EC₅₀) for the β2receptor.

Compound Preparation

10 mM/100% DMSO (dimethylsulfoxide) stock of compound is diluted torequired top dose in 4% DMSO. This top dose is used to construct a10-point semi-log dilution curve, all in 4% DMSO. Isoprenaline (Sigma,I-5627) was used as a standard in every experiment and for control wellson each plate. Data was expressed as % Isoprenaline response.

Cell Culture

CHO (Chinese Hamster Ovary) cells recombinantly expressing the human β2adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 andBouvier et al., Mol Pharmacol 33: 133-1391988 CHOhβ2) were grown inDulbeccos MEM/NUT MIX F12 (Gibco, 21331-020) supplemented with 10%foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mMglutamine (Sigma, G7513), 500 μg/ml geneticin (Sigma, G7034) and 10μg/ml puromycin (Sigma, P8833). Cells were seeded to give about 90%confluency for testing.

Assay Method

25 μl/well each dose of compound was transferred into a cAMP-Flashplate®(NEN, SMP004B), with 1% DMSO as basal controls and 100 nM Isoprenalineas max controls. This was diluted 1:2 by the addition of 25 μl/well PBS.Cells were trypsinised (0.25% Sigma, T4049), washed with PBS (Gibco,14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to give1×10⁶ cells/ml CHOhB2. Compounds were incubated with 50 μu/well cellsfor 1 hour. Cells were then lysed by the addition of 100 μl/welldetection buffer (NEN, SMP004B) containing 0.18 μCi/ml ¹²⁵I-cAMP (NEN,NEX-130) and plates were incubated at room temperature for a further 2hours. The amount of ¹²⁵I-CAMP bound to the Flashplate® was quantifiedusing a Topcount NXT (Packard), normal counting efficiency for 1 minute.Dose-response data was expressed as % Isoprenaline activity and fittedusing a four parameter sigmoid fit.

It has thus been found that the compounds of formula (1) according tothe present invention that are illustrated in examples 1 to 65 aboveshow a β2 cAMP EC₅₀ between 0.006 nM and 0.467 nM.

The results below illustrate the activity of the compounds of formula(1):

Cell based cAMP β2 activity Example Number (nM) 1 0.017 3 0.007 4 0.0125 0.024 6 0.007 7 0.028 8 0.010 10 0.114 12 0.009 13 0.013 15 0.056

1. A compound of formula (1):

wherein: the (CH₂)_(n)—C(═O)Q¹ group is substituted at the meta or paraposition of the phenyl ring to which it is attached; n is 1 or 2; Q¹ is

*-N(R⁸)-Q²-A; * indicates the point of attachment of Q¹ to the carbonylgroup; R¹, R², R³ and R⁴ are the same or different and are H, C₁-C₄alkyl, OR⁶, SR⁶, halo, CF₃, OCF₃, COOR⁶, SO₂NR⁶R⁷, CONR⁶R⁷, NR⁶R⁷ orNHCOR⁶; provided that at least two of R¹, R², R³ and R⁴ in thedefinition of Q¹ are H; R⁸ is H or C₁-C₄ alkyl; p is 1 or 2; Q² is asingle bond or C₁-C₄ alkylene; A is pyridyl or a group of formula

R⁵ is H, C₁-C₄ alkyl, OR⁶, SR⁶, halo, CF₃, OCF₃, COOR⁶, SO₂NR⁶R⁷,CONR⁶R⁷, NR⁶R⁷ or NHCOR⁶; provided that at least 2 of R¹, R², R³, R⁴ andR⁵ in the definition of A are H; R⁶ and R⁷ are the same or different andare H or C₁-C₄ alkyl; or an isomer, tautomer or isotope thereof or apharmaceutically acceptable salt of said compound, isomer, tautomer orisotope.
 2. A compound of claim 1 wherein Q¹ is *-NH-Q²-A; Q² is C₁-C₄alkylene; and A is


3. A compound of claim 2 wherein R¹, R², R³, R⁴ and R⁵ are the same ordifferent and are H, C₁-C₄ alkyl, OR⁶, Cl, F, CF₃, OCF₃, COOR⁶ orSO₂NR⁶R⁷, provided at least two of R¹, R², R³, R⁴ and R⁵ in thedefinition of A are H; and R⁶ and R⁷ are the same or different and are Hor C₁-C₄ alkyl.
 4. A compound of claim 3 wherein R¹, R², R³, R⁴ and R⁵are the same or different and are H, CH₃, OH, OCH₃, OCH₂CH₃, Cl, F, CF₃,OCF₃, COOH or SO₂NH₂, provided at least two of R¹, R², R³, R⁴ and R⁵ inthe definition of A are H.
 5. A compound of claim 4 wherein at leastthree of R¹, R², R³, R⁴ and R⁵ are H.
 6. A compound of claim 1 whereinQ¹ is *-NH-Q²-A; Q² is C₁-C₄ alkylene; and A is pyridin-2-yl.
 7. Acompound of claim 1 wherein Q² is —CH₂—, —(CH₂)₂—, —(CH₂)₃— or—CH(CH₃)—.
 8. A compound of claim 1 wherein Q² is —CH₂—.
 9. A compoundof claim 1 wherein Q¹ is


10. A compound of claim 9 wherein R¹, R², R³ and R⁴ are the same ordifferent and are H or OR⁷, provided at least 2 of R¹ to R⁴ are equal toH.
 11. A compound of claim 1 wherein Q¹ is


12. A compound of claim 1 wherein n is
 1. 13. A compound of claim 1wherein n is
 2. 14. The (R,R)-stereoisomer of a compound of claim
 1. 15.A compound of claim 1 wherein the (CH₂)_(n)—C(═O)Q¹ group is substitutedat the meta position. 16.N-(2,6-Dimethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-(2-ethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-(2-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-indan-2-yl-acetamide;N-(3,4-dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-[4-(aminosulfonyl)benzyl]-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(pyridin-2-ylmethyl)-acetamide;4-{(2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetylamino)-methyl}-benzamide;N-(3,4-dimethoxybenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(4-trifluoromethoxybenzyl)-acetamide;N-(2-chloro,6-fluorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-(3,4-dimethylbenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N[2-fluoro-5-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[(2R)-2-hydroxy-2(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-(2,6-dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-N-(2-phenylethyl)acetamide;N-benzyl-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-(3,5-dichlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide;N-(4-chlorobenzyl)-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}-phenyl)-acetamide;4-{([2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetyl]-amino)-methyl}-benzoicacid;2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1R)-1-phenylethyl]acetamide;4-{(1R)-2-[((1R)-2-{3-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxyethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;4-{(1R)-2-[((1R)-2-{3-[2-(7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxyethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;N-[2-(4-chlorophenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;N[2-(4-ethylphenyl)ethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;N-(1,1-dimethyl-2-phenylethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;N[2-(3,4-dimethoxyphenyl)ethyl]-2-{3-[2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;N-(3,4-difluorobenzyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;4-{(1R)-2-[((1R)-2-{3-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxyethyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylacetamide;2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(1-naphthylmethyl)acetamide;N-(3,4-dichlorobenzyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-5(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-pyridin-2-ylethyt)acetamide;2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(2R)-2-phenylpropyl]acetamide;N-benzyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide;N-[3-(4-fluorophenyl)propyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;N-(2,6-dichlorobenzyl)-3-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanamide;N-(2,6-dimethoxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;N-(2-ethoxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;N-(3,4-dimethylbenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;N-(2,3-dihydro-1H-inden-2-yl)-3-{3-[(2RI)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;4-{(1R)-2-[((1R)-2-{3-[3-(3,4-dihydrolsoquinolin-2(1H)-yl)-3-oxopropyl]phenyl}-1methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;N-(2-chloro-6-fluorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;N-(2-chlorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyI}-N-(pyridin-2-ylmethyl)propanamide;N-(2-chlorobenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propy]phenyl}-N-(pyridin-2-ylmethyl)propanamide;N-benzyl-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)propanamide;3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(3-phenylpropyl)propanamide;4-{(1R)-2-[((1R)-2-{3-[3-(1,3-dihydro-2H-isoindol-2-yl)-3-oxopropyl]phenyl}-1-methylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;N-[2-fluoro-5-(trifluoromethyl)benzyl]-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;N-(2-hydroxybenzyl)-3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanamide;3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-phenylpropanamide;N-benzyl-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl-amino]propyl}phenyl)acetamide;2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]propyl}phenyl)-N-(3-phenyl-propyl)acetamide;2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]propyl}phenyl)-N-indan-2-yl-acetamide;1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)ethanone;N-(2-hydroxybenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]propyl}phenyl)-acetamide;N-(3-chlorobenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)-acetamide;N-(4-chlorobenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)-acetamide;2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(2-methoxybenzyl)-acetamide;2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(3-methoxybenzyl)acetamide;2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-propyl}phenyl)-N-(4-methoxybenzyl)-acetamide;N-(2,6-dimethoxybenzyl)-2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)-acetamide;2-(4-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]propyl}phenyl)-N-(pyridin-2-ylmethyl)acetamide;N-[2-fluoro-5-(trifluoromethyl)benzyl]-2-{4-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;or2-{4-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-phenylethyl)acetamide.17. A process for preparing a compound of claim 1 or a pharmaceuticallyacceptable salt thereof comprising the step of coupling an acid offormula (2):

with an amine of formula (3), (3′) or (3″): NH₂-Q²-A (3),


18. A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient or additive.